Interaction with DNA polymerase eta is required for nuclear accumulation of REV1 and suppression of spontaneous mutations in human cells.


Defects in the gene encoding human Poleta result in xeroderma ...
Defects in the gene encoding human Poleta result in xeroderma pigmentosum variant (XP-V), an inherited cancer-prone syndrome. Poleta catalyzes efficient and accurate translesion DNA synthesis (TLS) past UV-induced lesions. In addition to Poleta, human cells have multiple TLS polymerases such as Poliota, Polkappa, Polzeta and REV1. REV1 physically interacts with other TLS polymerases, but the physiological relevance of the interaction remains unclear. Here we developed an antibody that detects the endogenous REV1 protein and found that human cells contain about 60,000 of REV1 molecules per cell as well as Poleta. In un-irradiated cells, formation of nuclear foci by ectopically expressed REV1 was enhanced by the co-expression of Poleta. Importantly, the endogenous REV1 protein accumulated at the UV-irradiated areas of nuclei in Poleta-expressing cells but not in Poleta-deficient XP-V cells. UV-irradiation induced nuclear foci of REV1 and Poleta proteins in both S-phase and G1 cells, suggesting that these proteins may function both during and outside S phase. We reconstituted XP-V cells with wild-type Poleta or with Poleta mutants harboring substitutions in phenylalanine residues critical for interaction with REV1. The REV1-interaction-deficient Poleta mutant failed to promote REV1 accumulation at sites of UV-irradiation, yet (similar to wild-type Poleta) corrected the UV sensitivity of XP-V cells and suppressed UV-induced mutations. Interestingly however, spontaneous mutations of XP-V cells were only partially suppressed by the REV1-interaction deficient mutant of Poleta. Thus, Poleta-REV1 interactions prevent spontaneous mutations, probably by promoting accurate TLS past endogenous DNA lesions, while the interaction is dispensable for accurate Poleta-mediated TLS of UV-induced lesions.




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