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Mechanisms of DNA repair by human DNA polymerase lambda

Final Activity Report Summary - DNA REPAIR BY POL? (Mechanisms of DNA repair by human DNA polymerase lambda)

Human DNA polymerase lambda is a recently identified DNA repair polymerase whose biochemical properties are partly similar to those of Pol beta, suggesting a role of Pol beta in DNA repair. Indeed, as Pol beta, Pol lambda has an intrinsic dRP lyase, an activity that is critical for the BER pathway. Unlike Pol beta, Pol lambda contains an N-terminal BRCT domain, required for a stable interaction with non-homologous end-joining (NHEJ) factors, which suggests the involvement of Pol lambda in double-strand break (DSB) repair. Moreover, the interaction of Pol lambda with PCNA and its capacity to extend base-pairs containing different kinds of DNA lesions, suggest also a role in damage tolerance, collaborating in translesion synthesis.

By comparing normal and tumoral samples, we identified and characterised a single nucleotide polymorphism (SNP) in human Pol lambda, resulting in amino acid change Arg to Trp in codon 438 (R438W). Interestingly, an elevated expression of this natural variant produces a significant increase in mutation frequency in vivo. In agreement with a causal effect, in vitro enzyme activity assays of both Arg and Trp 438 allelic variants showed a decrease in the fidelity of the W438 variant. Resolution of the 3D-structure of this natural variant of human Pol lambda allows discussing the molecular basis of this mutator W438 variant. Therefore, besides the more well-known loss-of-function mutations, polymorphic variants in DNA repair genes could substantially alter the overall DNA repair capacity, increasing the risk of mutations associated to repairing damaged DNA. Cancer-association studies of this Trp438 polymorphic variant were carried out, indicating a significant association of this natural mutator variant with rectal cancer.