DNA polymerase zeta contributes to heterochromatin replication to prevent genome instability

• Published in: The EMBO journal Vol. 40; no. 21; pp. e104543 - n/a
• Main Authors: Ben Yamin, Barbara, Ahmed‐Seghir, Sana, Tomida, Junya, Despras, Emmanuelle, Pouvelle, Caroline, Yurchenko, Andrey, Goulas, Jordane, Corre, Raphael, Delacour, Quentin, Droin, Nathalie, Dessen, Philippe, Goidin, Didier, Lange, Sabine S, Bhetawal, Sarita, Mitjavila‐Garcia, Maria Teresa, Baldacci, Giuseppe, Nikolaev, Sergey, Cadoret, Jean Charles, Wood, Richard D, Kannouche, Patricia L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02.11.2021; Springer Nature B.V; EMBO Press; John Wiley and Sons Inc
• Subjects: Animals; Cancer; Cell Line; Cell Line, Transformed; Cell Proliferation; Chemical synthesis; Chromobox Protein Homolog 5 - genetics; Chromobox Protein Homolog 5 - metabolism; Chromosomal Instability; Chromosomes; Deoxyribonucleic acid; Dimers; DNA; DNA - genetics; DNA - metabolism; DNA biosynthesis; DNA Breaks, Double-Stranded; DNA damage; DNA polymerase; DNA Replication; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; DNA-directed DNA polymerase; DNA-Directed DNA Polymerase - genetics; DNA-Directed DNA Polymerase - metabolism; EMBO09; EMBO13; Embryo, Mammalian; Embryogenesis; Embryonic growth stage; Embryonic Stem Cells - cytology; Embryonic Stem Cells - metabolism; Epigenesis, Genetic; Epigenetics; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Expression Regulation, Developmental; Genes; Genomes; Genomic instability; HeLa Cells; Heterochromatin; Heterochromatin - chemistry; Heterochromatin - metabolism; Histones; Humans; Inactivation; Life Sciences; Mice; Mice, Inbred C57BL; Mice, Transgenic; NIH 3T3 Cells; Repair; Replication; Replication forks; replication timing; REV3L; Signal Transduction; TLS polymerase; Transcription; REV3L; DNA replication; TLS polymerase; replication timing; heterochromatin; TLS polymerase Subject Categories Chromatin; Transcription & Genomics; Recombination & Repair
• ISSN: 0261-4189; 1460-2075; 1460-2075
• DOI: 10.15252/embj.2020104543

The DNA polymerase zeta (Polζ) plays a critical role in bypassing DNA damage. REV3L, the catalytic subunit of Polζ, is also essential in mouse embryonic development and cell proliferation for reasons that remain incompletely understood. In this study, we reveal that REV3L protein interacts with heterochromatin components including repressive histone marks and localizes in pericentromeric regions through direct interaction with HP1 dimer. We demonstrate that Polζ/REV3L ensures progression of replication forks through difficult‐to‐replicate pericentromeric heterochromatin, thereby preventing spontaneous chromosome break formation. We also find that Rev3l ‐deficient cells are compromised in the repair of heterochromatin‐associated double‐stranded breaks, eliciting deletions in late‐replicating regions. Lack of REV3L leads to further consequences that may be ascribed to heterochromatin replication and repair‐associated functions of Polζ, with a disruption of the temporal replication program at specific loci. This is correlated with changes in epigenetic landscape and transcriptional control of developmentally regulated genes. These results reveal a new function of Polζ in preventing chromosome instability during replication of heterochromatic regions. Synopsis Translesion synthesis DNA polymerase ζ (Polζ), with its catalytic subunit REV3L, is known to also limit DNA breaks in proliferating mammalian genomes, but specific consequences for replication and repair have remained unknown. This work demonstrates specific REV3L functions in limiting breaks and structural variations in heterochromatin. Inactivation of REV3L impairs replication fork speed at pericentromeres, disrupts replication timing near heterochromatin, and increases breaks and structural variations in heterochromatic regions. Polζ is targeted to heterochromatin via direct interaction with HP1. REV3L loss correlates with changes in the epigenetic landscape and transcriptional control of developmentally‐regulated genes. Graphical Abstract HP1‐mediated targeting of REVL3, the catalytic subunit of translesion synthesis Polζ, influences replication fork progression and epigenetic and transcriptional landscapes of developmentally‐regulated genes.