8ui7

Structural highlights

Function

ATAD5_HUMAN Has an important role in DNA replication and in maintaining genome integrity during replication stress (PubMed:15983387, PubMed:19755857). Involved in a RAD9A-related damage checkpoint, a pathway that is important in determining whether DNA damage is compatible with cell survival or whether it requires cell elimination by apoptosis (PubMed:15983387). Modulates the RAD9A interaction with BCL2 and thereby induces DNA damage-induced apoptosis (PubMed:15983387). Promotes PCNA deubiquitination by recruiting the ubiquitin-specific protease 1 (USP1) and WDR48 thereby down-regulating the error-prone damage bypass pathway (PubMed:20147293). As component of the ATAD5 RFC-like complex, regulates the function of the DNA polymerase processivity factor PCNA by unloading the ring-shaped PCNA homotrimer from DNA after replication during the S phase of the cell cycle (PubMed:23277426, PubMed:23937667). This seems to be dependent on its ATPase activity (PubMed:23277426). Plays important roles in restarting stalled replication forks under replication stress, by unloading the PCNA homotrimer from DNA and recruiting RAD51 possibly through an ATR-dependent manner (PubMed:31844045). Ultimately this enables replication fork regression, breakage, and eventual fork restart (PubMed:31844045). Both the PCNA unloading activity and the interaction with WDR48 are required to efficiently recruit RAD51 to stalled replication forks (PubMed:31844045). Promotes the generation of MUS81-mediated single-stranded DNA-associated breaks in response to replication stress, which is an alternative pathway to restart stalled/regressed replication forks (PubMed:31844045).^{[1] [2] [3] [4] [5] [6]}

References

1. ↑ Ishii H, Inageta T, Mimori K, Saito T, Sasaki H, Isobe M, Mori M, Croce CM, Huebner K, Ozawa K, Furukawa Y. Frag1, a homolog of alternative replication factor C subunits, links replication stress surveillance with apoptosis. Proc Natl Acad Sci U S A. 2005 Jul 5;102(27):9655-60. PMID:15983387 doi:10.1073/pnas.0504222102
2. ↑ Sikdar N, Banerjee S, Lee KY, Wincovitch S, Pak E, Nakanishi K, Jasin M, Dutra A, Myung K. DNA damage responses by human ELG1 in S phase are important to maintain genomic integrity. Cell Cycle. 2009 Oct 1;8(19):3199-207. PMID:19755857 doi:10.4161/cc.8.19.9752
3. ↑ Lee KY, Yang K, Cohn MA, Sikdar N, D'Andrea AD, Myung K. Human ELG1 regulates the level of ubiquitinated proliferating cell nuclear antigen (PCNA) through Its interactions with PCNA and USP1. J Biol Chem. 2010 Apr 2;285(14):10362-9. PMID:20147293 doi:10.1074/jbc.M109.092544
4. ↑ Lee KY, Fu H, Aladjem MI, Myung K. ATAD5 regulates the lifespan of DNA replication factories by modulating PCNA level on the chromatin. J Cell Biol. 2013 Jan 7;200(1):31-44. PMID:23277426 doi:10.1083/jcb.201206084
5. ↑ Shiomi Y, Nishitani H. Alternative replication factor C protein, Elg1, maintains chromosome stability by regulating PCNA levels on chromatin. Genes Cells. 2013 Nov;18(11):946-59. PMID:23937667 doi:10.1111/gtc.12087
6. ↑ Park SH, Kang N, Song E, Wie M, Lee EA, Hwang S, Lee D, Ra JS, Park IB, Park J, Kang S, Park JH, Hohng S, Lee KY, Myung K. ATAD5 promotes replication restart by regulating RAD51 and PCNA in response to replication stress. Nat Commun. 2019 Dec 16;10(1):5718. PMID:31844045 doi:10.1038/s41467-019-13667-4