Abstract
Translesion synthesis (TLS) polymerases are specialized DNA polymerases capable of inserting nucleotides opposite DNA lesions that escape removal by dedicated DNA repair pathways. TLS polymerases allow cells to complete DNA replication in the presence of damage, thereby preventing checkpoint activation, genome instability, and cell death. Here, we characterize functional knockouts for polh-1 and polk-1, encoding the Caenorhabditis elegans homologs of the Y-family TLS polymerases η and κ. POLH-1 acts at many different DNA lesions as it protects cells against a wide range of DNA damaging agents, including UV, γ-irradiation, cisplatin, and methyl methane sulphonate (MMS). POLK-1 acts specifically but redundantly with POLH-1 in protection against methylation damage. Importantly, both polymerases play a prominent role early in embryonic development to allow fast replication of damaged genomes. Contrary to observations in mammalian cells, we show that neither POLH-1 nor POLK-1 is required for homologous recombination (HR) repair of DNA double-strand breaks. A genome-wide RNAi screen for genes that protect the C. elegans genome against MMS–induced DNA damage identified novel components in DNA damage bypass in the early embryo. Our data suggest SUMO-mediated regulation of both POLH-1 and POLK-1, and point towards a previously unrecognized role of the nuclear pore in regulating TLS.
Highlights
IntroductionDNA damaging agents from both endogenous and exogenous sources can induce replication-blocking DNA lesions that threaten cell cycle progression and, cell viability
DNA damaging agents from both endogenous and exogenous sources can induce replication-blocking DNA lesions that threaten cell cycle progression and, cell viability. To remove these DNA lesions cells are equipped with various specialized repair mechanisms [1], including nucleotide excision repair (NER) that deals with helix-distorting obstructions [2]
Specialized translesion synthesis (TLS) polymerases are capable of bypassing DNA lesions without repairing them
Summary
DNA damaging agents from both endogenous and exogenous sources can induce replication-blocking DNA lesions that threaten cell cycle progression and, cell viability. To remove these DNA lesions cells are equipped with various specialized repair mechanisms [1], including nucleotide excision repair (NER) that deals with helix-distorting obstructions [2]. Unrepaired DNA damage may delay replication and cell cycle progression. In the nematode Caenorhabditis elegans a delay in replication is detrimental for the developmental program; timing of cell division is fixed and strictly regulated by the homologues of the checkpoint genes CHK1 and ATR [4]. Early embryos of C. elegans appear to be remarkably resistant to DNA damaging agents, suggesting an efficient way to prevent the induction of replication stress by DNA damage [6]
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