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.

SCAI promotes error‐free repair of DNA interstrand crosslinks via the Fanconi anemia pathway

“…In addition to its crucial function in protecting against erroneous repair of ICLs, our data suggest that SCAI may also impact TLS as part of the REV1-Polf complex. Consistently, a recent study on the function of Polf at heterochromatin regions also reported an interaction between SCAI and REV3 (Yamin et al, 2021). In egg extracts, SCAI immunodepletion co-depletes REV3, suggesting tight REV3-SCAI association, and SCAI is likely a novel constitutive component of REV1-Polf (note that the converse is not true as some SCAI is not associated with REV1-Polf).…”

Catalytic and non-catalytic functions of DNA polymerase kappa in translesion DNA synthesis

“…In contrast to Polκ knockouts, Rev3–/– mouse embryonic stem cells are not viable (Lange et al, 2012), which suggests that Polζ possesses Polκ independent functions. Interestingly, Rev3 also functions beyond TLS by facilitating DNA replication through heterochromatic regions (Ben Yamin et al, 2021), which could account for its essential role.…”

Epidemiology of Δ8THC-Related Carcinogenesis in USA: A Panel Regression and Causal Inferential Study

“…Both single-and double-stranded breaks (SSB and DSB) are a common feature of cell karyotype studies after cannabis exposure [7][8][9][10]12,13,99]. It therefore becomes important in the present context to note that the epigenome plays an often determinative role in influencing or selecting the site of DNA breakage generally [118][119][120][121][122][123][124][125][126][127][128][129][130][131], during meiotic crossing over [132][133][134][135][136][137][138][139], in the immune gene hypervariable region [140][141][142][143][144][145][146], and in oncogenic pathways [120,123,124,[147][148][149][150][151][152][153]…”

“…This tumor almost invariably involves the development of an isochromosome 12p. Its presence is explained by the concept of presumptive pericentromeric chromatin dysregulation as the dysregulated pericentromeric epigenome presumably facilitates the aberrant scission of the chromosome at the centromere, forming the isochromosome through the interactions between the epigenome and the genome as described above [118][119][120][121][122][123][124][125][126][127][128][129][130][131]. The presence of KIT and KRAS (and to a lesser extent NRAS) on chromosome 12 then confers a growth advantage on the mutant clone, and malignant tumorigenesis is the end result of this process continued in the context of the gross re-sculpting of the chromosomal landscape by repeated cycles of the breakage-fusion-bridge cycle across multiple cell divisions that accumulate over time.…”