DNA polymerase zeta contributes to heterochromatin replication to prevent genome instability.

Abstract

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.

• Authors: Barbara Ben Yamin, Sana Ahmed-Seghir, Junya Tomida, Emmanuelle Despras, Caroline Pouvelle, Andrey Yurchenko, Jordane Goulas, Raphael Corre, Quentin Delacour, Nathalie Droin, Philippe Dessen, Didier Goidin, Sabine S Lange, Sarita Bhetawal, Maria Teresa Mitjavila-Garcia, Giuseppe Baldacci, Sergey Nikolaev, Jean Charles Cadoret, Richard D Wood, Patricia L Kannouche
• Journal: The EMBO journal (EMBO J) Vol. 40 Issue 21 Pg. e104543 (11 02 2021) ISSN: 1460-2075 [Electronic] England
• PMID: 34533226 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: © 2021 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

Chemical References

• DNA-Binding Proteins
• Heterochromatin
• Chromobox Protein Homolog 5
• DNA
• DNA-Directed DNA Polymerase
• REV3L protein, mouse

Topics

• Animals
• Cell Line
• Cell Line, Transformed
• Cell Proliferation
• Chromobox Protein Homolog 5 (genetics, metabolism)
• Chromosomal Instability
• DNA (genetics, metabolism)
• DNA Breaks, Double-Stranded
• DNA Replication
• DNA-Binding Proteins (genetics, metabolism)
• DNA-Directed DNA Polymerase (genetics, metabolism)
• Embryo, Mammalian
• Embryonic Stem Cells (cytology, metabolism)
• Epigenesis, Genetic
• Fibroblasts (cytology, metabolism)
• Gene Expression Regulation, Developmental
• HeLa Cells
• Heterochromatin (chemistry, metabolism)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• NIH 3T3 Cells
• Signal Transduction