MDC1

Last updated
MDC1
Protein MDC1 PDB 2ado.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases MDC1 , NFBD1, mediator of DNA damage checkpoint 1
External IDs OMIM: 607593 MGI: 3525201 HomoloGene: 67092 GeneCards: MDC1
Orthologs
SpeciesHumanMouse
Entrez

9656

240087

Ensembl

ENSMUSG00000061607

UniProt

Q14676

Q5PSV9

RefSeq (mRNA)

NM_014641

NM_001010833

RefSeq (protein)

NP_055456

Location (UCSC) Chr 6: 30.7 – 30.72 Mb Chr 17: 36.15 – 36.17 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

Mediator of DNA damage checkpoint protein 1 is a 2080 amino acid long protein that in humans is encoded by the MDC1 gene [5] [6] [7] located on the short arm (p) of chromosome 6. MDC1 protein is a regulator of the Intra-S phase and the G2/M cell cycle checkpoints and recruits repair proteins to the site of DNA damage. It is involved in determining cell survival fate in association with tumor suppressor protein p53. This protein also goes by the name Nuclear Factor with BRCT Domain 1 (NFBD1).

Function

Role in DNA damage response

The MDC1 gene encodes the MDC1 nuclear protein which is part of the DNA damage response (DDR) pathway, the mechanism through which eukaryotic cells respond to damaged DNA, specifically DNA double-strand breaks (DSB) that are caused by ionizing radiation or chemical clastogens. [8] The DDR of mammalian cells is made up of kinases, and mediator/adaptors factors. [9] In mammalian cells the DDR is a network of pathways made up of proteins that function as either kinases, or and mediator/adaptors that recruit the kinases to their phosphorylation targets, these factors work together to detect DNA damage, and signal the repair mechanism as well as activating cell cycle checkpoints. [9] The MDC1s role in DDR is to function both as a mediator/adaptor protein mediating a complex of other DDR proteins at the site of DNA damage [9] and repairing DNA damage through its PST domain. [10]

When a cell is exposed to ionizing radiation, its chromatin can be damaged with DSB, triggering the DDR which starts with the MRN complex recruiting ATM kinase to the exposed H2AX histones on the damaged DNA. ATM phosphorylates the C-terminus of the H2AX histone (phosphorylated H2AX histones are commonly noted as γH2AX), and they become an epigenetic flag that highlights the site of DNA damage . The SDT domain of the MDC1 protein is phosphorylated by caseine kinase 2 (CK2) which allows it to bind another MRN complex, the MDC1 protein can sense the DNA damage by binding to the γH2AX flag through its BRCT domain and brings the bound MRN complex to the site of damaged DNA and it facilitates the recruitment and retention of another ATM kinase. The second ATM kinase phosphorylates the TQXF domain on MDC1 which allows it to recruit the E3 ubiquitin ligase RNF8, which will ubiquitinate the histones near the DSB which initiates further ubiquitination of the chromatin around the site of damage by other factors of the DDR. This aggregation of DDR factors and concentration of phosphorylated and ubiquitinated histones is called a DNA damage foci or ionizing radiation-induced foci [9] and the main role of MDC1 is to coordinate the creation of DNA damage foci. This protein is required to activate the intra-S phase and G2/M phase cell cycle checkpoints in response to DNA damage.

Role in apoptosis

MDC1 has anti-apoptotic properties by directly inhibiting the apoptotic activity of the tumor suppressing protein p53. DNA damage can induce apoptosis when the ATM kinase and Chk2 phosphorylate p53 on its Ser-15 and Ser-20 residues which activates p53 and stabilizes it by allowing it to dissociate from the E3 ubiquitin protein ligase MDM2. [11] MDC1 can execute its anti-apoptotic activity by inhibiting p53 in two ways. The MDC1 protein can bind to the n-terminus of p53 through its BRC1 domain which blocks p53 transactivation domain. MDC1 can also inactivate p53 by reducing the phosphorylation levels of p53 Ser-15 residues necessary to p53 apoptotic activity. Studies on lung cancer cell lines (A549 cells) showed an increase in apoptosis in response to genotoxic agents when MDC1 protein levels were reduced with siRNA. [11]

Role in meiosis

In female mammals, a unique characteristic of meiosis, not observed in other types of cells, is the prolonged arrest during the prophase stage of meiosis I. [12] In oocytes, DNA double-strand breaks can be repaired during meiosis I by a process involving microtubule-dependent recruitment of the CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes. [12]

Loss of MDC1 protein

Inhibition or loss of MDC1 protein through studies with siRNA on human cells or knockout studies in mice have shown several defects at both the cellular and organismal level. Mice lacking MDC1 are smaller, have infertile males, are radiosensitive, and are more susceptible to tumors. Knock out MDC1 mice cells and silenced human cells were radiosensitive, failed to initiate Intra-S phase and G2/M checkpoints, failed to produce ionizing radiation-induced foci had poor phosphorylation by the DRR kinases (ATM, CHK1, CHK2), defects in homologous recombination. Human cells with silenced MDC1 also displayed random plasmid integration, reduced apoptosis, and slowed mitosis. [9]

Interactions

MDC1 has been shown to interact with:

MDC1 also binds to mRNA or polyadenylated RNA in the nucleus. [15]

Protein structure

The MDC1 protein contains the following domains listed in order from N-terminal to C-terminal:

FHA domain
Unlike the FHA domains on other DRR factors, the FHA domain on MDC1 is not well-characterized. It has been implicated in DSB repair, Intra-S phase and G2/M checkpoints but the specific mechanism is yet to be determined. The FHA domain does have a few putative MDC1-FHA interacting factors such as ATM, CHK2, and RAD51. [9]
SDT domain
When the SDT domain is phosphorylated it can bind the MRN complex (composed of MRE11/RAD50/NBS1) [16] and is responsible for keeping the MRN complex associated with the DSB chromatin. [17] [18] [19] This domain along with NBS1 of the MRN complex are necessary for the activation of intra-S-phase and the G2/M checkpoints, however their role in the molecular mechanism of checkpoint control has not been resolved. [9]
TQXF domain
This domain is characterized by four threonine-glutamine then a phenylalanine at the 3+ position. [9] ATM phosphorylates this domain allowing it to bind RNF8 an E3 ubiquitin ligase. This MDC1/RNF8 coupling then facilitates the recruitment of other DDR factors such as RNF168, 53BP1, and BRCA1. [9] TQXF is important for proper passage through the G2/M checkpoint, however the molecular mechanism through which MDC1 and RNF8 regulate the G2/M checkpoint has not yet been resolved.
PST domain
The PST domain is composed of repeats of a proline-serine-threonine motif. This domain plays a role in DNA repair by both homologous recombination and by Non-homologous end joining, however the mechanism through which it facilitates repair of damaged DNA is not yet known. [10]
BRCT domain
The BRCT domain on MDC1 directly binds to the γH2AX of damaged chromatin. The BRCT domain creates an α/β fold which extends from the C-terminus of MDC1 through a linker region. It preferentially binds to phosphorylated Ser residues followed by Glu, Tyr, motif on γH2AX. [20] This domain also binds to anaphase-promoting complex (APC/C) which is an E3 ubiquitin ligase that degrades cyclins. [21] The BRCT domain is involved in the regulation of the decatenation checkpoint at the end of replication by binding Topo IIα this arrest the cell in the G2 cycle until the sister chromatin have completely separated. [22] The BRCT domain also interacts the tumor suppressor p53 and inhibits p53 by blocking its transactivation domain, as well as aiding in MDM2 inactivation of p53. [11]

Regulation

MDC1 is indirectly down regulated by the oncogene AKT1. AKT1 activates expression of the microRNA-22 (miR-22) which targets the 3' end of MDC1 mRNA inhibiting translation. Aberrant overexpression of AKT1, which is observed in several cancers including breast, lung and prostate, results in reduced production of MDC1 and subsequently a destabilization of the genome and increased tumorigenicity. [23]

Role in cancer

MDC1 is a putative tumor suppressor. Knockout studies in mice have shown an increase in tumor development when MDC1 is lost. Reduction in MDC1 protein levels has been observed in a large number of breast and lung carcinomas. [24] [25] Several studies on various human cancer cell lines including the A549 cell human lung carcinoma line, [11] multiple esophageal cancer cell lines (TE11, YES2, YES5), [26] and cervical cancer cell lines (HeLa, SiHa, and CaSki) [27] showed increased sensitivity to anti-cancer drugs (adriamycin and cisplatin), when endogenous MDC1 protein levels were knockdown with siRNA. Because of MDC1s involvement in several pathways that are often misappropriated by cancer cells including the cell cycle checkpoints, DDR, and p53 tumor suppression, cancer treatments that target MDC1 have the potential to be potent radiosensitizer and chemosensitizer.

Related Research Articles

p53 Mammalian protein found in Homo sapiens

p53, also known as Tumor protein P53, cellular tumor antigen p53, or transformation-related protein 53 (TRP53) is a regulatory protein that is often mutated in human cancers. The p53 proteins are crucial in vertebrates, where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome" because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene.

<span class="mw-page-title-main">ATM serine/threonine kinase</span> Mammalian protein found in Homo sapiens

ATM serine/threonine kinase or Ataxia-telangiectasia mutated, symbol ATM, is a serine/threonine protein kinase that is recruited and activated by DNA double-strand breaks, oxidative stress, topoisomerase cleavage complexes, splicing intermediates, R-loops and in some cases by single-strand DNA breaks. It phosphorylates several key proteins that initiate activation of the DNA damage checkpoint, leading to cell cycle arrest, DNA repair or apoptosis. Several of these targets, including p53, CHK2, BRCA1, NBS1 and H2AX are tumor suppressors.

<span class="mw-page-title-main">Cell cycle checkpoint</span> Control mechanism in the eukaryotic cell cycle

Cell cycle checkpoints are control mechanisms in the eukaryotic cell cycle which ensure its proper progression. Each checkpoint serves as a potential termination point along the cell cycle, during which the conditions of the cell are assessed, with progression through the various phases of the cell cycle occurring only when favorable conditions are met. There are many checkpoints in the cell cycle, but the three major ones are: the G1 checkpoint, also known as the Start or restriction checkpoint or Major Checkpoint; the G2/M checkpoint; and the metaphase-to-anaphase transition, also known as the spindle checkpoint. Progression through these checkpoints is largely determined by the activation of cyclin-dependent kinases by regulatory protein subunits called cyclins, different forms of which are produced at each stage of the cell cycle to control the specific events that occur therein.

<span class="mw-page-title-main">G1/S transition</span> Stage in cell cycle

The G1/S transition is a stage in the cell cycle at the boundary between the G1 phase, in which the cell grows, and the S phase, during which DNA is replicated. It is governed by cell cycle checkpoints to ensure cell cycle integrity and the subsequent S phase can pause in response to improperly or partially replicated DNA. During this transition the cell makes decisions to become quiescent, differentiate, make DNA repairs, or proliferate based on environmental cues and molecular signaling inputs. The G1/S transition occurs late in G1 and the absence or improper application of this highly regulated checkpoint can lead to cellular transformation and disease states such as cancer.

<span class="mw-page-title-main">Nibrin</span> Protein-coding gene in the species Homo sapiens

Nibrin, also known as NBN or NBS1, is a protein which in humans is encoded by the NBN gene.

<span class="mw-page-title-main">CHEK2</span> Protein-coding gene in humans

CHEK2 is a tumor suppressor gene that encodes the protein CHK2, a serine-threonine kinase. CHK2 is involved in DNA repair, cell cycle arrest or apoptosis in response to DNA damage. Mutations to the CHEK2 gene have been linked to a wide range of cancers.

<span class="mw-page-title-main">H2AFX</span> Histone protein from the H2A family

H2A histone family member X is a type of histone protein from the H2A family encoded by the H2AFX gene. An important phosphorylated form is γH2AX (S139), which forms when double-strand breaks appear.

Chromatin remodeling is the dynamic modification of chromatin architecture to allow access of condensed genomic DNA to the regulatory transcription machinery proteins, and thereby control gene expression. Such remodeling is principally carried out by 1) covalent histone modifications by specific enzymes, e.g., histone acetyltransferases (HATs), deacetylases, methyltransferases, and kinases, and 2) ATP-dependent chromatin remodeling complexes which either move, eject or restructure nucleosomes. Besides actively regulating gene expression, dynamic remodeling of chromatin imparts an epigenetic regulatory role in several key biological processes, egg cells DNA replication and repair; apoptosis; chromosome segregation as well as development and pluripotency. Aberrations in chromatin remodeling proteins are found to be associated with human diseases, including cancer. Targeting chromatin remodeling pathways is currently evolving as a major therapeutic strategy in the treatment of several cancers.

<span class="mw-page-title-main">CHEK1</span> Protein-coding gene in humans

Checkpoint kinase 1, commonly referred to as Chk1, is a serine/threonine-specific protein kinase that, in humans, is encoded by the CHEK1 gene. Chk1 coordinates the DNA damage response (DDR) and cell cycle checkpoint response. Activation of Chk1 results in the initiation of cell cycle checkpoints, cell cycle arrest, DNA repair and cell death to prevent damaged cells from progressing through the cell cycle.

<span class="mw-page-title-main">RAD9A</span> Protein-coding gene in the species Homo sapiens

Cell cycle checkpoint control protein RAD9A is a protein that in humans is encoded by the RAD9A gene.Rad9 has been shown to induce G2 arrest in the cell cycle in response to DNA damage in yeast cells. Rad9 was originally found in budding yeast cells but a human homolog has also been found and studies have suggested that the molecular mechanisms of the S and G2 checkpoints are conserved in eukaryotes. Thus, what is found in yeast cells are likely to be similar in human cells.

<span class="mw-page-title-main">TP53BP1</span> Protein-coding gene in the species Homo sapiens

Tumor suppressor p53-binding protein 1 also known as p53-binding protein 1 or 53BP1 is a protein that in humans is encoded by the TP53BP1 gene.

<span class="mw-page-title-main">GADD45A</span> Protein-coding gene in the species Homo sapiens

Growth arrest and DNA-damage-inducible protein GADD45 alpha is a protein that in humans is encoded by the GADD45A gene.

<span class="mw-page-title-main">TOPBP1</span> Protein-coding gene in the species Homo sapiens

DNA topoisomerase 2-binding protein 1 (TOPBP1) is a scaffold protein that in humans is encoded by the TOPBP1 gene.

<span class="mw-page-title-main">PLK3</span> Protein-coding gene in the species Homo sapiens

Polo-like kinase 3 (Drosophila), also known as PLK3, is an enzyme which in humans is encoded by the PLK3 gene.

<span class="mw-page-title-main">RBBP8</span> Protein-coding gene in the species Homo sapiens

Retinoblastoma-binding protein 8 is a protein that in humans is encoded by the RBBP8 gene.

<span class="mw-page-title-main">RNF8</span> Protein-coding gene in the species Homo sapiens

E3 ubiquitin-protein ligase RNF8 is an enzyme that in humans is encoded by the RNF8 gene. RNF8 has activity both in immune system functions and in DNA repair.

<span class="mw-page-title-main">Meiotic recombination checkpoint</span>

The meiotic recombination checkpoint monitors meiotic recombination during meiosis, and blocks the entry into metaphase I if recombination is not efficiently processed.

<span class="mw-page-title-main">BRCT domain</span>

BRCA1 C Terminus (BRCT) domain is a family of evolutionarily related proteins. It is named after the C-terminal domain of BRCA1, a DNA-repair protein that serves as a marker of breast cancer susceptibility.

<span class="mw-page-title-main">G2-M DNA damage checkpoint</span>

The G2-M DNA damage checkpoint is an important cell cycle checkpoint in eukaryotic organisms that ensures that cells don't initiate mitosis until damaged or incompletely replicated DNA is sufficiently repaired. Cells with a defective G2-M checkpoint will undergo apoptosis or death after cell division if they enter the M phase before repairing their DNA. The defining biochemical feature of this checkpoint is the activation of M-phase cyclin-CDK complexes, which phosphorylate proteins that promote spindle assembly and bring the cell to metaphase.

DNA damage is an alteration in the chemical structure of DNA, such as a break in a strand of DNA, a nucleobase missing from the backbone of DNA, or a chemically changed base such as 8-OHdG. DNA damage can occur naturally or via environmental factors, but is distinctly different from mutation, although both are types of error in DNA. DNA damage is an abnormal chemical structure in DNA, while a mutation is a change in the sequence of base pairs. DNA damages cause changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly. The DNA damage response (DDR) is a complex signal transduction pathway which recognizes when DNA is damaged and initiates the cellular response to the damage.

References

  1. 1 2 3 ENSG00000237095, ENSG00000137337, ENSG00000206481, ENSG00000234012, ENSG00000231135, ENSG00000228575, ENSG00000225589 GRCh38: Ensembl release 89: ENSG00000224587, ENSG00000237095, ENSG00000137337, ENSG00000206481, ENSG00000234012, ENSG00000231135, ENSG00000228575, ENSG00000225589 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000061607 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Ozaki T, Nagase T, Ichimiya S, Seki N, Ohiri M, Nomura N, Takada N, Sakiyama S, Weber BL, Nakagawara A (Sep 2000). "NFBD1/KIAA0170 is a novel nuclear transcriptional transactivator with BRCT domain". DNA Cell Biol. 19 (8): 475–485. doi:10.1089/10445490050128403. PMID   10975465.
  6. 1 2 Stewart GS, Wang B, Bignell CR, Taylor AM, Elledge SJ (Feb 2003). "MDC1 is a mediator of the mammalian DNA damage checkpoint". Nature. 421 (6926): 961–966. Bibcode:2003Natur.421..961S. doi:10.1038/nature01446. PMID   12607005. S2CID   4410773.
  7. ↑ "Entrez Gene: MDC1 mediator of DNA damage checkpoint 1".
  8. ↑ Zhou BB, Elledge SJ (Nov 2000). "The DNA damage response: putting checkpoints in perspective". Nature. 408 (6811): 433–439. Bibcode:2000Natur.408..433Z. doi:10.1038/35044005. PMID   11100718. S2CID   4419141.
  9. 1 2 3 4 5 6 7 8 9 Jungmichel S, Stucki M (Aug 2010). "MDC1: The art of keeping things in focus" (PDF). Chromosoma. 119 (4): 337–349. doi:10.1007/s00412-010-0266-9. PMID   20224865. S2CID   20619554.
  10. 1 2 Lou Z, Chen BP, Asaithamby A, Minter-Dykhouse K, Chen DJ, Chen J (Nov 2004). "MDC1 regulates DNA-PK autophosphorylation in response to DNA damage". J Biol Chem. 279 (45): 46359–62. doi: 10.1074/jbc.c400375200 . PMID   15377652.
  11. 1 2 3 4 Nakanishi M, Ozaki T, Yamamoto H, Hanamoto T, Kikuchi H, Furuya K, Asaka M, Delia D, Nakagawara A (Aug 2007). "NFBD1/MDC1 associates with p53 and regulates its function at the crossroad between cell survival and death in response to DNA damage". J Biol Chem. 282 (31): 22993–3004. doi: 10.1074/jbc.m611412200 . PMID   17535811.
  12. 1 2 Leem J, Kim JS, Oh JS (June 2023). "Oocytes can repair DNA damage during meiosis via a microtubule-dependent recruitment of CIP2A-MDC1-TOPBP1 complex from spindle pole to chromosomes". Nucleic Acids Research. 51 (10): 4899–4913. doi:10.1093/nar/gkad213. PMC   10250218 . PMID   36999590.
  13. ↑ Lou Z, Minter-Dykhouse K, Wu X, Chen J (Feb 2003). "MDC1 is coupled to activated CHK2 in mammalian DNA damage response pathways". Nature. 421 (6926): 957–61. Bibcode:2003Natur.421..957L. doi:10.1038/nature01447. PMID   12607004. S2CID   4411622.
  14. 1 2 Xu X, Stern DF (Oct 2003). "NFBD1/MDC1 regulates ionizing radiation-induced focus formation by DNA checkpoint signaling and repair factors". FASEB J. 17 (13): 1842–8. doi: 10.1096/fj.03-0310com . PMID   14519663. S2CID   24870579.
  15. ↑ Conrad T, Albrecht AS, de Melo Costa VR, Sauer S, Meierhofer D, Ørom UA (2016-01-01). "Serial interactome capture of the human cell nucleus". Nature Communications. 7: 11212. Bibcode:2016NatCo...711212C. doi:10.1038/ncomms11212. PMC   4822031 . PMID   27040163.
  16. ↑ de Jager M, van Noort J, van Gent DC, Dekker C, Kanaar R, Wyman C (Nov 2001). "Human Rad50/Mre11 is a flexible complex that can tether DNA ends". Mol Cell. 8 (5): 1129–1135. doi: 10.1016/s1097-2765(01)00381-1 . PMID   11741547.
  17. ↑ Bekker-Jensen S, Lukas C, Kitagawa R, Melander F, Kastan MB, Bartek J, Lukas J (Apr 2006). "Spatial organization of the mammalian genome surveillance machinery in response to DNA strand breaks". J Cell Biol. 173 (2): 195–206. doi:10.1083/jcb.200510130. PMC   2063811 . PMID   16618811.
  18. ↑ Goldberg M, Stucki M, Falck J, D'amours D, Rahman D, Pappin D, Bartek J, Jackson S (Feb 2003). "MDC1 is required for the intra-S- phase DNA damage checkpoint". Nature. 421 (6926): 952–956. Bibcode:2003Natur.421..952G. doi:10.1038/nature01445. PMID   12607003. S2CID   4301037.
  19. ↑ Lukas C, Melander F, Stucki M, Falck J, Bekker-Jensen S, Goldberg M, Lerenthal Y, Jackson S, Bartek J, Lukas J (Jul 2004). "Mdc1 couples DNA double-strand break recognition by Nbs1 with its H2AX- dependent chromatin retention". EMBO J. 23 (13): 2674–2683. doi:10.1038/sj.emboj.7600269. PMC   449779 . PMID   15201865.
  20. ↑ Lou Z, Minter-Dykhouse K, Franco S, Gostissa M, Rivera MA, Celeste A, Manis JP, van Deursen J, Nussenzweig A, Paull TT, Alt FW, Chen J (Jan 2006). "MDC1 maintains genomic stability by participating in the amplification of ATM-dependent DNA damage signals". Mol Cell. 21 (2): 187–200. doi: 10.1016/j.molcel.2005.11.025 . PMID   16427009.
  21. ↑ Coster G, Hayouka Z, Argaman L, Strauss C, Friedler A, Brandeis M, Goldberg M (Sep 2007). "The DNA damage response mediator MDC1 directly interacts with the anaphase-promoting complex/cyclosome". J Biol Chem. 282 (44): 32053–32064. doi: 10.1074/jbc.m705890200 . PMID   17827148.
  22. ↑ Luo K, Yuan J, Chen J, Lou Z (Feb 2009). "Topoisomerase IIalpha controls the decatenation checkpoint". Nat Cell Biol. 11 (2): 204–210. doi:10.1038/ncb1828. PMC   2712943 . PMID   19098900.
  23. ↑ Lee JH, Park SJ, Jeong SY, Kim MJ, Jun S, Lee HS, Chang IY, Lim SC, Yoon SP, Yong J, and You HJ (Apr 2015). "MicroRNA-22 Suppresses DNA Repair and Promotes Genomic Instability through Targeting of MDC1". Cancer Research. 75 (7): 1298–1310. doi: 10.1158/0008-5472.CAN-14-2783 . PMID   25627978.
  24. ↑ Minter-Dykhouse K, Ward I, Huen SY, Chen J, Lou Z (Jun 2008). "Distinct versus overlapping functions of MDC1 and 53BP1 in DNA damage response and tumorigenesis". J Cell Biol. 181 (5): 727–735. doi:10.1083/jcb.200801083. PMC   2396806 . PMID   18504301.
  25. ↑ Bartkova J, Hořejsí Z, Sehested M, Nesland JM, Rajpert-De Meyts E, Skakkebæk NE, Stucki M, Jackson S, Lukas J, Bartek J (Jun 2007). "DNA damage response mediators MDC1 and 53BP1: constitu- tive activation and aberrant loss in breast and lung cancer, but not in testicular germ cell tumours". Oncogene. 26 (53): 7414–7422. doi: 10.1038/sj.onc.1210553 . PMID   17546051.
  26. ↑ Yang M, Bu Y, Wang C, Liu G, Song F (Sep 2010). "Growth inhibition, morphology change, and cell cycle alterations in NFBD1-depleted human esophageal cancer cells". Mol Cell Biochem. 342 (1–2): 1–6. doi:10.1007/s11010-010-0460-3. PMID   20364298. S2CID   27389033.
  27. ↑ Yuan C, Bu Y, Wang C, Yi F, Yang Z, Huang X, Cheng L, Liu G, Wang Y, Song F (Jan 2010). "NFBD1/MDC1 is a protein of oncogenic potential in human cervical cancer". Mol Cell Biochem. 359 (1–2): 333–46. doi:10.1007/s11010-011-1027-7. PMID   21853275. S2CID   16067442.

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