Proliferating cell nuclear antigen (PCNA)-binding protein C1orf124 is a regulator of translesion synthesis.
DNA damage-induced proliferating cell nuclear antigen (PCNA) ubiquitination serves as the key event mediating post-replication repair. Post-replication repair involves either translesion synthesis (TLS) or damage avoidance via template switching. In this study, we have identified and characterized C1orf124 as a regulator of TLS. C1orf124 co-localizes and interacts with unmodified and mono-ubiquitinated PCNA at UV light-induced damage sites, which require the PIP box and UBZ domain of C1orf124. C1orf124 also binds to the AAA-ATPase valosin-containing protein via its SHP domain, and cellular resistance to UV radiation mediated by C1orf124 requires its interactions with valosin-containing protein and PCNA. Interestingly, C1orf124 binds to replicative DNA polymerase POLD3 and PDIP1 under normal conditions but preferentially associates with TLS polymerase η (POLH) upon UV damage. Depletion of C1orf124 compromises PCNA monoubiquitination, RAD18 chromatin association, and RAD18 localization to UV damage sites. Thus, C1orf124 acts at multiple steps in TLS, stabilizes RAD18 and ubiquitinated PCNA at damage sites, and facilitates the switch from replicative to TLS polymerase to bypass DNA lesion.
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Gargi
G
Ghosal
Justin Wai-Chung
JW
Leung
Binoj C
BC
Nair
Ka-Wing
KW
Fong
Junjie
J
Chen
D004249:DNA Damage; D004258:DNA Polymerase III / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000235:genetics / Q000378:metabolism*; D034702:RNA-Binding Protein FUS / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases; D054875:Ubiquitination; D014466:Ultraviolet Rays / Q000009:adverse effects; D000099270:Y-Family DNA Polymerases
D004258:DNA Polymerase III; D004268:DNA-Binding Proteins; D004259:DNA-Directed DNA Polymerase; D009687:Nuclear Proteins; D018809:Proliferating Cell Nuclear Antigen; D034702:RNA-Binding Protein FUS; D044767:Ubiquitin-Protein Ligases; C439978:KCTD13 protein, human; C485954:RAD18 protein, human; C574636:SPRTN protein, human; C435720:POLD3 protein, human; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases