BRCA1-A complex subunit RAP80 is a protein that in humans is encoded by the UIMC1 gene. [5] [6]
BRCA1-A complex subunit RAP80 is a protein that in humans is encoded by the UIMC1 gene. [5] [6]
RAP80, the protein product of the UIMC1 gene, is a core component of the deubiquitin complex BRCA1-A. [7] Other core components of the BRCA1-A complex are the BRCC36 protein (BRCC3 gene), BRE protein (BRE (gene)), and MERIT40 protein (BABAM1 gene). [7]
BRCA1, as distinct from BRCA1-A, is employed in the repair of chromosomal damage with an important role in the error-free homologous recombinational (HR) repair of DNA double-strand breaks. Sequestration of BRCA1 away from the DNA damage site suppresses homologous recombination and redirects the cell in the direction of repair by the process of non-homologous end joining (NHEJ). [7] The role of BRCA1-A complex appears to be to bind BRCA1 with high affinity and withdraw it away from the site of DNA damage to the periphery where it remains sequestered, thus promoting NHEJ in preference to HR.
DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules that encode its genome. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Many of these lesions cause structural damage to the DNA molecule and can alter or eliminate the cell's ability to transcribe the gene that the affected DNA encodes. Other lesions induce potentially harmful mutations in the cell's genome, which affect the survival of its daughter cells after it undergoes mitosis. As a consequence, the DNA repair process is constantly active as it responds to damage in the DNA structure. When normal repair processes fail, and when cellular apoptosis does not occur, irreparable DNA damage may occur. This can eventually lead to malignant tumors, or cancer as per the two-hit hypothesis.
Non-homologous end joining (NHEJ) is a pathway that repairs double-strand breaks in DNA. It is called "non-homologous" because the break ends are directly ligated without the need for a homologous template, in contrast to homology directed repair (HDR), which requires a homologous sequence to guide repair. NHEJ is active in both non-dividing and proliferating cells, while HDR is not readily accessible in non-dividing cells. The term "non-homologous end joining" was coined in 1996 by Moore and Haber.
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.
DNA-dependent protein kinase, catalytic subunit, also known as DNA-PKcs, is an enzyme that in humans is encoded by the gene designated as PRKDC or XRCC7. DNA-PKcs belongs to the phosphatidylinositol 3-kinase-related kinase protein family. The DNA-Pkcs protein is a serine/threonine protein kinase consisting of a single polypeptide chain of 4,128 amino acids.
NEDD8 is a protein that in humans is encoded by the NEDD8 gene. This ubiquitin-like (UBL) protein becomes covalently conjugated to a limited number of cellular proteins, in a process called NEDDylation similar to ubiquitination. Human NEDD8 shares 60% amino acid sequence identity to ubiquitin. The primary known substrates of NEDD8 modification are the cullin subunits of cullin-based E3 ubiquitin ligases, which are active only when NEDDylated. Their NEDDylation is critical for the recruitment of E2 to the ligase complex, thus facilitating ubiquitin conjugation. NEDD8 modification has therefore been implicated in cell cycle progression and cytoskeletal regulation.
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.
DNA repair protein RAD50, also known as RAD50, is a protein that in humans is encoded by the RAD50 gene.
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.
NEDD8-activating enzyme E1 regulatory subunit is a protein that in humans is encoded by the NAE1 gene.
Origin recognition complex subunit 3 is a protein that in humans is encoded by the ORC3 (ORC3L) gene.
E3 ubiquitin-protein ligase FANCL is an enzyme that in humans is encoded by the FANCL gene.
Ubiquitin-conjugating enzyme E2 H is a protein that in humans is encoded by the UBE2H gene.
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.
BRCA1-A complex subunit BRE is a protein that in humans is encoded by the BRE gene.
Lys-63-specific deubiquitinase BRCC36 is an enzyme that in humans is encoded by the BRCC3 gene.
Partner and localizer of BRCA2, also known as PALB2 or FANCN, is a protein which in humans is encoded by the PALB2 gene.
BRCA1-A complex subunit MERIT40 is a protein that in humans is encoded by the BABAM1 gene.
DNA replication complex GINS protein PSF2 is a protein that in humans is encoded by the GINS2 gene.
Zinc finger CCHC domain-containing protein 8 is a protein that in humans is encoded by the ZCCHC8 gene.
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).
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