Migrating bubble synthesis promotes mutagenesis through lesions in its template

Beth Osia, Jerzy Twarowski, Tyler Jackson, Kirill Lobachev, Liping Liu, Anna Malkova

Producción científica: Articlerevisión exhaustiva

7 Citas (Scopus)

Resumen

Break-induced replication (BIR) proceeds via a migrating D-loop for hundreds of kilobases and is highly mutagenic. Previous studies identified long single-stranded (ss) nascent DNA that accumulates during leading strand synthesis to be a target for DNA damage and a primary source of BIR-induced mutagenesis. Here, we describe a new important source of mutagenic ssDNA formed during BIR: the ssDNA template for leading strand BIR synthesis formed during D-loop migration. Specifically, we demonstrate that this D-loop bottom template strand (D-BTS) is susceptible to APOBEC3A (A3A)-induced DNA lesions leading to mutations associated with BIR. Also, we demonstrate that BIR-associated ssDNA promotes an additional type of genetic instability: replication slippage between microhomologies stimulated by inverted DNA repeats. Based on our results we propose that these events are stimulated by both known sources of ssDNA formed during BIR, nascent DNA formed by leading strand synthesis, and the D-BTS that we describe here. Together we report a new source of mutagenesis during BIR that may also be shared by other homologous recombination pathways driven by D-loop repair synthesis.

Idioma originalEnglish (US)
Páginas (desde-hasta)6870-6889
Número de páginas20
PublicaciónNucleic acids research
Volumen50
N.º12
DOI
EstadoPublished - jul 8 2022
Publicado de forma externa

ASJC Scopus subject areas

  • Genetics

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