TY - JOUR

T1 - Error-prone bypass of DNA lesions during lagging-strand replication is a common source of germline and cancer mutations

AU - Seplyarskiy, Vladimir B.

AU - Akkuratov, Evgeny E.

AU - Akkuratova, Natalia

AU - Andrianova, Maria A.

AU - Nikolaev, Sergey I.

AU - Bazykin, Georgii A.

AU - Adameyko, Igor

AU - Sunyaev, Shamil R.

PY - 2019/1

Y1 - 2019/1

N2 - Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.

AB - Studies in experimental systems have identified a multitude of mutational mechanisms including DNA replication infidelity and DNA damage followed by inefficient repair or replicative bypass. However, the relative contributions of these mechanisms to human germline mutation remain unknown. Here, we show that error-prone damage bypass on the lagging strand plays a major role in human mutagenesis. Transcription-coupled DNA repair removes lesions on the transcribed strand; lesions on the non-transcribed strand are preferentially converted into mutations. In human polymorphism we detect a striking similarity between mutation types predominant on the non-transcribed strand and on the strand lagging during replication. Moreover, damage-induced mutations in cancers accumulate asymmetrically with respect to the direction of replication, suggesting that DNA lesions are resolved asymmetrically. We experimentally demonstrate that replication delay greatly attenuates the mutagenic effect of ultraviolet irradiation, confirming that replication converts DNA damage into mutations. We estimate that at least 10% of human mutations arise due to DNA damage.

KW - Cells, Cultured

KW - DNA Damage/genetics

KW - DNA Repair/genetics

KW - DNA Replication/genetics

KW - DNA/genetics

KW - Germ-Line Mutation/genetics

KW - Humans

KW - Mutagenesis/genetics

KW - Neoplasms/genetics

KW - Polymorphism, Single Nucleotide/genetics

KW - Transcription, Genetic/genetics

KW - MUTAGENESIS

KW - SIGNATURES

KW - MECHANISMS

KW - REVEAL

KW - DAMAGE

KW - SOMATIC MUTATIONS

KW - NUCLEOTIDE EXCISION-REPAIR

KW - ORIGIN

KW - DE-NOVO MUTATIONS

KW - APOBEC3B

UR - http://www.scopus.com/inward/record.url?scp=85058128183&partnerID=8YFLogxK

UR - http://www.mendeley.com/research/errorprone-bypass-dna-lesions-during-laggingstrand-replication-common-source-germline-cancer-mutatio

U2 - 10.1038/s41588-018-0285-7

DO - 10.1038/s41588-018-0285-7

M3 - Letter

C2 - 30510240

AN - SCOPUS:85058128183

VL - 51

SP - 36

EP - 41

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 1

ER -