FANC proteins

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FANC proteins are a network of at least 15 proteins that are associated with a cell process known as the Fanconi anemia. [1] [2] [3] [4] [5] [6]

Contents

History

Fanconi anemia was first described in 1927 by Guido Fanconi, a Swiss pediatrician. [7] It is a chromosome instability syndrome characterized by the progressiveness of bone marrow failure and of cancer proneness. [7]

Properties

The FA genes that code for the FANC proteins are a part of the caretaker group of cancer genes that prevent the buildup of mutations and chromosome abnormalities. [7] The multiple FANC proteins come together to add up to the FANC/BRCA pathway. [7]

Components

There are a large number of FANC proteins that participate in the FA pathway. [5] It has a nuclear complex also known as the ‘FA core complex’ which is formed by the interaction of FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, FANCM and the accessory proteins (FAAP20, FAAP24, and FAAP100). [5] These accessory proteins are also called Fanconi anemia associated proteins (FAAPs). [6] There is also a group called the anchor complex which consists of FANCM, FAAP24, MHF1 (FAAP16/ CENP-S), and MHF2 (FAAP10/ CENP-X). [5] The FANC proteins that are not a part of the core complex are FANCD1, FANCJ, and FANCN. [5]

Components include:

Function

They are involved in DNA replication and damage response. [8] FANC proteins are also in charge of repairing complex DNA interstrand cross-linking lesions and maintaining the genomic stability during DNA replication. [5] DNA cross-linking is what hinders transcription and replication from occurring in the cell so it is important that the cell has methods to repair at every stage of the cell cycle. [5] There are multiple different repair pathways but the FA pathway is the one that involves the FANC proteins. [5] When cross-link is detected, then the ataxia-telangiectasia and RAD3-related protein will mediate the phosphorylation (P) of the FA core complex. [5] This phosphorylated FA core complex is what is required to have a successful monoubiquitination of the two components that form the FANCI–D2 complex. [5] Each of the proteins of the FA core complex are needed for this phosphorylation step except for FANCM. [5] When a typical cell senses DNA damage it targets the monoubiquitinated isoform of FANCI–D2 to the chromatid with DNA damage, which is the cross-link. [5] Studies have also shown that there is a connection between the FA DNA repair pathway and stem cell regulation but it is still unclear. [5] FANC proteins also play a role in redox signaling and repair of oxidative DNA damages. [9] Recent studies have dove into the FANC protein, FANCJ, and its enzymatic function along with its roles in repair. [5] Other studies have shown the correlation between the FANC pathway and multiple other protein post translational modifications from ubiquitin-like families. [4]

Pathogenesis

A mutation in 13 FANC genes can result in Fanconi anemia (FA), which is a cancer-prone chromosome instability disorder. [4] [10] [9] Fanconi anemia occurs when there is a biallelic mutation that inactivates the genes that are in charge of the replication stress associated DNA damage response. [4] Dysfunction of FANC proteins has been associated with a range of conditions, including the rendering of cell hypersensitivity to a type of DNA damage known as DNA interstrand cross-links (ICL) and defective DNA repair. [6] [9] [10] FANC protein mutations have also lead to reduced fertility and predisposition to cancers like breast cancer and myeloid leukaemia. [5] [11] [12] FANC proteins FANCD1 (BRCA2), FANCJ (BRIP), and FANCN (PALB2) have even been identified as the breast cancer susceptibility proteins. [5] If a cell were to lack the FANC gene to code for these proteins then the cell would show a hypersensitive phenotype following H2O2 treatment. [9]

FANC proteins are related to BRCA. [7]

FANC proteins are required to promote BLM-mediated anaphase. [7]

FANC proteins also interacts with BRCA1. [5]

FANC proteins also interacts with LIG4. [5]

FANC proteins also interacts with DNA-PKcs. [5]

FANC proteins also interacts with Ku70. [5]

FANC proteins also interacts with Ku80. [5]

FANC proteins also interacts with FAN. [5]

FANC proteins also interacts with XPF. [5]

FANCC protein interacts with cdc2. [5]

FANCC protein interacts with PKR. [5]

FANCC protein interactS with p53. [5]

FANC protein FANCD1 is also known as BRCA2. [5]

FANC protein FANCJ is also known as BRIP1. [5]

FANC protein FANCN is also known as PALB2. [5]

FANC protein FANCO is also known as RAD51C. [5]

FANC protein FANCP is also known as SLX4. [5]

Related Research Articles

<span class="mw-page-title-main">Fanconi anemia</span> Medical condition

Fanconi anemia (FA) is a rare, AR, genetic disease resulting in impaired response to DNA damage in the FA/BRCA pathway. Although it is a very rare disorder, study of this and other bone marrow failure syndromes has improved scientific understanding of the mechanisms of normal bone marrow function and development of cancer. Among those affected, the majority develop cancer, most often acute myelogenous leukemia (AML), MDS, and liver tumors. 90% develop aplastic anemia by age 40. About 60–75% have congenital defects, commonly short stature, abnormalities of the skin, arms, head, eyes, kidneys, and ears, and developmental disabilities. Around 75% have some form of endocrine problem, with varying degrees of severity. 60% of FA is FANC-A, 16q24.3, which has later onset bone marrow failure.

<span class="mw-page-title-main">BRCA2</span> Gene known for its role in breast cancer

BRCA2 and BRCA2 are a human gene and its protein product, respectively. The official symbol and the official name are maintained by the HUGO Gene Nomenclature Committee. One alternative symbol, FANCD1, recognizes its association with the FANC protein complex. Orthologs, styled Brca2 and Brca2, are common in other vertebrate species. BRCA2 is a human tumor suppressor gene, found in all humans; its protein, also called by the synonym breast cancer type 2 susceptibility protein, is responsible for repairing DNA.

<span class="mw-page-title-main">Fanconi anemia, complementation group C</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group C protein is a protein that in humans is encoded by the FANCC gene. This protein delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA. Mutations in this gene result in Fanconi anemia, a human rare disorder characterized by cancer susceptibility and cellular sensitivity to DNA crosslinks and other damages.

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

Fanconi anaemia, complementation group A, also known as FAA, FACA and FANCA, is a protein which in humans is encoded by the FANCA gene. It belongs to the Fanconi anaemia complementation group (FANC) family of genes of which 12 complementation groups are currently recognized and is hypothesised to operate as a post-replication repair or a cell cycle checkpoint. FANCA proteins are involved in inter-strand DNA cross-link repair and in the maintenance of normal chromosome stability that regulates the differentiation of haematopoietic stem cells into mature blood cells.

<span class="mw-page-title-main">FANCD2</span> Protein-coding gene in the species Homo sapiens

Fanconi anemia group D2 protein is a protein that in humans is encoded by the FANCD2 gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, FANCN and FANCO.

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

Fanconi anemia group G protein is a protein that in humans is encoded by the FANCG gene.

<span class="mw-page-title-main">ERCC4</span> Protein-coding gene in the species Homo sapiens

ERCC4 is a protein designated as DNA repair endonuclease XPF that in humans is encoded by the ERCC4 gene. Together with ERCC1, ERCC4 forms the ERCC1-XPF enzyme complex that participates in DNA repair and DNA recombination.

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

Fanconi anemia group F protein is a protein that in humans is encoded by the FANCF gene.

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

Fanconi anemia, complementation group E protein is a protein that in humans is encoded by the FANCE gene. The Fanconi anemia complementation group (FANC) currently includes FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, and FANCL. Fanconi anemia is a genetically heterogeneous recessive disorder characterized by cytogenetic instability, hypersensitivity to DNA cross-linking agents, increased chromosomal breakage, and defective DNA repair. The members of the Fanconi anemia complementation group do not share sequence similarity; they are related by their assembly into a common nuclear protein complex. This gene encodes the protein for complementation groufcrp E.

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

E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.

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

Fanconi anemia group B protein is a protein that in humans is encoded by the FANCB gene.

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

Fanconi anemia, complementation group I (FANCI) also known as KIAA1794, is a protein which in humans is encoded by the FANCI gene. Mutations in the FANCI gene are known to cause Fanconi anemia.

<span class="mw-page-title-main">PALB2</span> Protein-coding gene in the species Homo sapiens

Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.

<span class="mw-page-title-main">FANCM</span> Mammalian protein found in Homo sapiens

Fanconi anemia, complementation group M, also known as FANCM is a human gene. It is an emerging target in cancer therapy, in particular cancers with specific genetic deficiencies.

Alan D. D'Andrea is an American cancer researcher and the Fuller American Cancer Society Professor of Radiation Oncology at Harvard Medical School. D'Andrea's research at the Dana Farber Cancer Institute focuses on chromosome instability and cancer susceptibility. He is currently the director of the Center for DNA Damage and Repair and the director of the Susan F. Smith Center for Women's Cancer.

<span class="mw-page-title-main">Hereditary cancer syndrome</span> Inherited genetic condition that predisposes a person to cancer

A hereditary cancer syndrome is a genetic disorder in which inherited genetic mutations in one or more genes predispose the affected individuals to the development of cancer and may also cause early onset of these cancers. Hereditary cancer syndromes often show not only a high lifetime risk of developing cancer, but also the development of multiple independent primary tumors.

Chromosomal instability (CIN) is a type of genomic instability in which chromosomes are unstable, such that either whole chromosomes or parts of chromosomes are duplicated or deleted. More specifically, CIN refers to the increase in rate of addition or loss of entire chromosomes or sections of them. The unequal distribution of DNA to daughter cells upon mitosis results in a failure to maintain euploidy leading to aneuploidy. In other words, the daughter cells do not have the same number of chromosomes as the cell they originated from. Chromosomal instability is the most common form of genetic instability and cause of aneuploidy.

<span class="mw-page-title-main">FAN1</span> Protein-coding gene in the species Homo sapiens

FANCD2/FANCI-associated nuclease 1 (KIAA1018) is an enzyme that in humans is encoded by the FAN1 gene. It is a structure dependent endonuclease. It is thought to play an important role in the Fanconi Anemia (FA) pathway.

Agata Smogorzewska is a Polish-born scientist. She is an associate professor at Rockefeller University, heading the Laboratory of Genome Maintenance. Her work primarily focuses on DNA interstrand crosslink repair and the diseases resulting from deficiencies in this repair pathway, including Fanconi anemia and karyomegalic interstitial nephritis.

<span class="mw-page-title-main">Double-strand break repair model</span>

A double-strand break repair model refers to the various models of pathways that cells undertake to repair double strand-breaks (DSB). DSB repair is an important cellular process, as the accumulation of unrepaired DSB could lead to chromosomal rearrangements, tumorigenesis or even cell death. In human cells, there are two main DSB repair mechanisms: Homologous recombination (HR) and non-homologous end joining (NHEJ). HR relies on undamaged template DNA as reference to repair the DSB, resulting in the restoration of the original sequence. NHEJ modifies and ligates the damaged ends regardless of homology. In terms of DSB repair pathway choice, most mammalian cells appear to favor NHEJ rather than HR. This is because the employment of HR may lead to gene deletion or amplification in cells which contains repetitive sequences. In terms of repair models in the cell cycle, HR is only possible during the S and G2 phases, while NHEJ can occur throughout whole process. These repair pathways are all regulated by the overarching DNA damage response mechanism. Besides HR and NHEJ, there are also other repair models which exists in cells. Some are categorized under HR, such as synthesis-dependent strain annealing, break-induced replication, and single-strand annealing; while others are an entirely alternate repair model, namely, the pathway microhomology-mediated end joining (MMEJ).

References

  1. ↑ FANC+Proteins at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
  2. ↑ Naim V, Rosselli F (June 2009). "The FANC pathway and BLM collaborate during mitosis to prevent micro-nucleation and chromosome abnormalities". Nat. Cell Biol. 11 (6): 761–8. doi:10.1038/ncb1883. PMID   19465921. S2CID   330040.
  3. ↑ Hans D. Ochs; C. I. Edvard Smith; Jennifer Puck (2007). Primary immunodeficiency diseases: a molecular and genetic approach. Oxford University Press US. pp. 431–. ISBN   978-0-19-514774-2 . Retrieved 21 December 2010.
  4. 1 2 3 4 Thompson, Larry (2009). "Cellular and molecular consequences of defective Fanconi anemia proteins in replication-coupled DNA repair: Mechanistic insights". Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis. 668 (1–2): 54–72. doi:10.1016/j.mrfmmm.2009.02.003. PMC   2714807 . PMID   19622404.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 Gupta, S. "Fanconi Anemia Protein". Science Direct. Retrieved 28 November 2023.
  6. 1 2 3 "FANCA gene". Medlineplus. Retrieved 28 November 2023.
  7. 1 2 3 4 5 6 Naim, Valeria (2009). "The FANC pathway and mitosis: A replication legacy". Cell Cycle. 8 (18): 2907–2912. doi: 10.4161/cc.8.18.9538 . PMID   19729998. S2CID   37042438 . Retrieved 28 November 2023.
  8. ↑ Naim V, Rosselli F (September 2009). "The FANC pathway and mitosis: a replication legacy". Cell Cycle. 8 (18): 2907–11. doi: 10.4161/cc.8.18.9538 . PMID   19729998.
  9. 1 2 3 4 Park, Su-Jung (2004). "Oxidative Stress/Damage Induces Multimerization and Interaction of Fanconi Anemia Proteins". The Journal of Biological Chemistry. 279 (29): 30053–30059. doi: 10.1074/jbc.M403527200 . PMID   15138265 . Retrieved 28 November 2023.
  10. 1 2 Ting, Liu (2010). "FAN1 Acts with FANCI-FANCD2 to Promote DNA Interstrand Cross-Link Repair". Science. 329 (5992): 693–696. Bibcode:2010Sci...329..693L. doi: 10.1126/science.1192656 . PMID   20671156. S2CID   206527789 . Retrieved 28 November 2023.
  11. ↑ Renaudin, Xavier (2016). "The ubiquitin family meets the Fanconi anemia proteins". Mutation Research/Reviews in Mutation Research. 769: 36–46. doi:10.1016/j.mrrev.2016.06.004. PMID   27543315 . Retrieved 28 November 2023.
  12. ↑ Pichierri, Pietro (2004). "BLM and the FANC proteins collaborate in a common pathway in response to stalled replication forks". The EMBO Journal. 23 (15): 3154–3163. doi:10.1038/sj.emboj.7600277. PMC   514912 . PMID   15257300.


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