Function of heterochromatin protein 1 during DNA repair

Bártová, Eva; Malyšková, Barbora; Komůrková, Denisa; Legartová, Soňa; Suchánková, Jana; Krejčí, Jana; Kozubek, Stanislav

doi:10.1007/s00709-017-1090-3

Cited by 20 publications

(13 citation statements)

References 49 publications

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“…To learn more about the function of H4K20me3 at DNA lesions, we studied the level of H4K20me3 in G1, S, and G2 phases of the cell cycle. We recognized G1 and G2 phases according to the nuclear distribution pattern of H3S10 phosphorylation [ 29 ] and S phase according to the distribution pattern of proliferating cell nuclear antigen (PCNA), which recognizes DNA lesions in late S and G2 phases of the cell cycle [ 30 ]. In the G1 phase of the cell cycle, we found the highest level of H4K20me3 at DNA lesions; however, in the G2 phase, we observed a lower density of H4K20me3 at locally micro-irradiated chromatin ( Fig.…”

Section: Resultsmentioning

confidence: 99%

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H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions

Kovaříková

Legartová

Krejčí

et al. 2018

Aging

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Methylation of histones H4 at lysine 20 position (H4K20me), which is functional in DNA repair, represents a binding site for the 53BP1 protein. Here, we show a radiation-induced increase in the level of H4K20me3 while the levels of H4K20me1 and H4K20me2 remained intact. H4K20me3 was significantly pronounced at DNA lesions in only the G1 phase of the cycle, while this histone mark was reduced in very late S and G2 phases when PCNA was recruited to locally micro-irradiated chromatin. H4K20me3 was diminished in locally irradiated Suv39h1/h2 double knockout (dn) fibroblasts, and the same phenomenon was observed for H3K9me3 and its binding partner, the HP1β protein. Immunoprecipitation showed the existence of an interaction between H3K9me3-53BP1 and H4K20me3-53BP1; however, HP1β did not interact with 53BP1. Together, H3K9me3 and H4K20me3 represent epigenetic markers that are important for the function of the 53BP1 protein in non-homologous end joining (NHEJ) repair. The very late S phase represents the cell cycle breakpoint when a DDR function of the H4K20me3-53BP1 complex is abrogated due to recruitment of the PCNA protein and other DNA repair factors of homologous recombination to DNA lesions.

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Section: Resultsmentioning

confidence: 99%

“…9A, B ). Moreover, H4K20me3 is essential at DNA lesions, especially in the G1 phase of the cell cycle, but when the PCNA protein appeared at damaged chromatin in very late S phase [ 30 ], H4K20me3 was reduced ( Fig. 8A-D, 10A-D ).…”

Section: Discussionmentioning

confidence: 99%

H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions

Kovaříková

Legartová

Krejčí

et al. 2018

Aging

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“…HP1 is a well-established factor in the response to DSBs (Bartova, Malyskova et al, 2017), at least, in part through the retention of BRCA1 at DNA damage sites by HP1-γ (Wu et al, 2015). We confirmed these observations in the U2OS mCherry-LacR-FokI cells where depletion of HP1-γ, but neither HP1-α or -β significantly impaired the accumulation of BRCA1 at the focal DNA damage site (Fig.3E and Expanded View Fig.4D-E).…”

Section: Resultsmentioning

confidence: 99%

POGZ modulates the DNA damage response in a HP1-dependent manner

Heath

Findlay

et al. 2021

Preprint

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The heterochromatin protein HP1 plays a central role in the maintenance of genome stability, in particular by promoting homologous recombination (HR)-mediated DNA repair. However, little is still known about how HP1 is controlled during this process. Here, we describe a novel function of the POGO transposable element derived with ZNF domain protein (POGZ) in the regulation of HP1 during the DNA damage response in vitro. POGZ depletion delays the resolution of DNA double-strand breaks (DSBs) and correlates with an increased sensitivity to different DNA damaging agents, including the clinically-relevant Cisplatin and Talazoparib. Mechanistically, POGZ promotes homology-directed DNA repair pathways by retaining the BRCA1/BARD1 complex at DSBs, in a HP1-dependent manner. In vivo CRISPR inactivation of Pogz is embryonic lethal and Pogz haplo-insufficiency (Pogz+/Δ) results in a developmental delay, a deficit in intellectual abilities, a hyperactive behaviour as well as a compromised humoral immune response in mice, recapitulating the main clinical features of the White Sutton syndrome (WHSUS). Importantly, Pogz+/Δ mice are radiosensitive and accumulate DSBs in diverse tissues, including the spleen and the brain. Altogether, our findings identify POGZ as an important player in homology-directed DNA repair both in vitro and in vivo, with clinical implications for the WHSUS.

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“…Drosha is a double-stranded RNA-specific ribonuclease (RNase) III and a subunit of the microprocessor protein complex, contributes to DDR activation by generating small non-coding RNAs [22]. HP1BP3 (heterochromatin protein 1 binding protein 3) is a novel chromatin-binding protein [23]. HP1α, heterochromatin protein 1 isoform α, the main factor responsible for heterochromatin maintenance and gene silencing and is necessary for the binding of the main DNA damage-related protein 53BP1 at DNA repair foci [24].…”

Section: Flywch1 Is Localised In Nuclear Speckles and Colocalised With γH2axmentioning

confidence: 99%

FLYWCH1, a Multi-Functional Zinc Finger Protein Contributes to the DNA Repair Pathway

Almozyan

Coulton

Babaei‐Jadidi

et al. 2021

Cells

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Over recent years, several Cys2-His2 (C2H2) domain-containing proteins have emerged as critical players in repairing DNA-double strand breaks. Human FLYWCH1 is a newly characterised nuclear transcription factor with (C2H2)-type zinc-finger DNA-binding domains. Yet, our knowledge about FLYWCH1 is still in its infancy. This study explores the expression, role and regulation of FLYWCH1 in the context of DNA damage and repair. We provide evidence suggesting a potential contribution of FLYWCH1 in facilitating the recruitment of DNA-damage response proteins (DDRPs). We found that FLYWCH1 colocalises with γH2AX in normal fibroblasts and colorectal cancer (CRC) cell lines. Importantly, our results showed that enforced expression of FLYWCH1 induces the expression of γH2AX, ATM and P53 proteins. Using an ATM-knockout (ATMKO) model, we indicated that FLYWCH1 mediates the phosphorylation of H2AX (Ser139) independently to ATM expression. On the other hand, the induction of DNA damage using UV-light induces the endogenous expression of FLYWCH1. Conversely, cisplatin treatment reduces the endogenous level of FLYWCH1 in CRC cell lines. Together, our findings uncover a novel FLYWCH1/H2AX phosphorylation axis in steady-state conditions and during the induction of the DNA-damage response (DDR). Although the role of FLYWCH1 within the DDR machinery remains largely uncharacterised and poorly understood, we here report for the first-time findings that implicate FLYWCH1 as a potential participant in the DNA damage response signaling pathways.

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Function of heterochromatin protein 1 during DNA repair

Cited by 20 publications

References 49 publications

H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions

H3K9me3 and H4K20me3 represent the epigenetic landscape for 53BP1 binding to DNA lesions

POGZ modulates the DNA damage response in a HP1-dependent manner

FLYWCH1, a Multi-Functional Zinc Finger Protein Contributes to the DNA Repair Pathway

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