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.

中文翻译：

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DNA聚合酶zeta有助于异染色质复制以防止基因组不稳定

DNA 聚合酶 zeta (Polζ) 在绕过 DNA 损伤方面起着关键作用。REV3L 是 Polζ 的催化亚基，对于小鼠胚胎发育和细胞增殖也是必不可少的，原因尚不完全清楚。在这项研究中，我们揭示了 REV3L 蛋白与异染色质成分相互作用，包括抑制性组蛋白标记，并通过与 HP1 二聚体的直接相互作用定位在着丝粒周围区域。我们证明 Polζ/REV3L 通过难以复制的着丝粒周围异染色质确保复制叉的进展，从而防止自发的染色体断裂形成。我们还发现Rev3l- 缺陷细胞在修复异染色质相关双链断裂时受到损害，导致晚期复制区域的缺失。缺乏 REV3L 会导致进一步的后果，这可能归因于 Polζ 的异染色质复制和修复相关功能，破坏了特定位点的时间复制程序。这与表观遗传景观的变化和发育调节基因的转录控制有关。这些结果揭示了 Polζ 在防止异染色质区域复制过程中染色体不稳定方面的新功能。