5 years ago

Error-prone bypass of DNA lesions during lagging strand replication is a common source of germline and cancer mutations

Sunyaev, Nikolaev, M. A., V., S. R., S. I., Bazykin, Andrianova, Seplyarskiy, G. A.
Spontaneously occurring mutations are of great relevance in diverse fields including biochemistry, oncology, evolutionary biology, and human genetics. Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity as well as many forms of DNA damage followed by inefficient repair or replicative bypass1-4. However, the relative contributions of these mechanisms to human germline mutations remain completely unknown. Here, based on the mutational asymmetry with respect to the direction of replication and transcription, we suggest that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Asymmetry with respect to transcription is believed to be mediated by the action of transcription-coupled DNA repair (TC-NER). TC-NER selectively repairs DNA lesions on the transcribed strand; as a result, lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between transcriptional asymmetry and asymmetry with respect to replication fork direction. This parallels the observation that damage-induced mutations in human cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are asymmetrically resolved during replication. Data from XR-seq experiments5 and the analysis of cancers with defective NER corroborate the preferential error-prone bypass of DNA lesions on the lagging strand. The analysis of Damage-seq6 data suggests that DNA damage on the lagging strand persists longer than damage on the leading strand in the population of dividing cells. We estimate that at least 9% of human germline mutations arise due to DNA damage rather than replication infidelity. Counterintuitively, the number of these damage-induced mutations is expected to scale with the number of replications and, consequently, paternal age.

Publisher URL: http://biorxiv.org/cgi/content/short/200691v1

DOI: 10.1101/200691

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