Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

Soria, Gastón; Almouzni, Geneviève

doi:10.4161/cc.23215

Cited by 55 publications

(56 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, mice expressing only 10% of HP1β protein levels are indistinguishable from wild-type littermates [35], suggesting that the amount of HP1β required for survival is small [36]. Consistent with these results, knockdown of HP1β by specific RNAi in different cell types neither induces cell death nor alters cell cycle progression [37,38].…”

Section: Introductionsupporting

confidence: 72%

“…It is not clear, however, whether HP1β is required for cell survival or whether intrabody aggregation is responsible for cell death observed in about 60% of transfected cells. Thus, although we find that intrabody-mediated HP1β aggregation in the cytoplasm induces cell death, knockdown of HP1β by specific RNAi in different cell types neither induces cell death nor alters cell cycle progression [37,38]. Moreover, mice expressing only 10% of HP1β protein levels are indistinguishable from wild-type littermates [35] and displacement of HP1β from constitutive heterochromatin by using dominant negative HP1 constructs does not affect cell viability, suggesting that the amount of HP1β required for survival is small [59,53].…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

Cardinale

Filesi

Singh

et al. 2015

Experimental Cell Research

View full text Add to dashboard Cite

HighlightsIntrabodies against heterochromatin protein 1 β (HP1β) inhibit its traffic to the nucleus. Anti-HP1β intrabodies sequester HP1β in cytoplasmic aggregates. Anti-HP1β scFv causes co-aggregation of LBR and H3-H4 histones in the cytoplasm. Methylated histone H3 at K9 (Me9H3) is not affected by anti-HP1β scFv expression. Anti-HP1β scFv induces altered nuclear morphology and apoptosis. Diverting a Q2 protein from its intracellular location is a unique property of intrabodies. To interfere with the intracellular traffic of heterochromatin protein 1β (HP1β) in living cells, we have generated a cytoplasmic targeted anti-HP1β intrabody, specifically directed against the C-terminal portion of the molecule. HP1β is a conserved component of mouse and human constitutive heterochromatin involved in diverse nuclear functions including gene silencing, DNA repair and nuclear membrane assembly. We found that the anti-HP1β intrabody sequesters HP1β into cytoplasmic aggregates, inhibiting its traffic to the nucleus. Lamin B receptor (LBR) and a subset of core histones (H3/H4) are also specifically co-sequestered in the cytoplasm of anti-HP1β intrabody-expressing cells. Methylated histone H3 at K9 (Me9H3), a marker of constitutive heterochromatin, is not affected by the anti-HP1β intrabody expression. Hyper-acetylating conditions completely dislodge H3 from HP1β:LBR containing aggregates. The expression of anti-HP1β scFv fragments induces apoptosis, associated with an alteration of nuclear morphology. Both these phenotypes are specifically rescued either by overexpression of recombinant full length HP1β or by HP1β mutant containing the chromoshadow domain, but not by recombinant LBR protein. The HP1β-chromodomain mutant, on the other hand, does not rescue the phenotypes, but does compete with LBR for binding to HP1β. These findings provide new insights into the mode of action of cytoplasmic-targeted intrabodies and the interaction between HP1β and its binding partners involved in peripheral heterochromatin organisation.

show abstract

Section: Introductionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 94%

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

Cardinale

Filesi

Singh

et al. 2015

Experimental Cell Research

View full text Add to dashboard Cite

show abstract

“…Although chromatin opening occurs also in DSBs inflicted in euchromatin [54], there is increasing evidence that heterochromatin proteins are de novo recruited to DNA lesions outside of heterochromatin and exert a positive role in DNA repair [55][56][57][58][59]. Furthermore, transient condensation of chromatin surrounding a DSB by induction 150 Genome architecture and expression of H3K9me3 and HP1 recruitment was shown to be essential for ATM and ATR activation [60].…”

Section: Dna Repair Pathway Choice In Heterochromatinmentioning

confidence: 97%

Nuclear compartmentalization of DNA repair

Kalousi

Soutoglou

2016

Current Opinion in Genetics & Development

View full text Add to dashboard Cite

“…In Drosophila, cytological studies revealed that H3K9me-deficient mutants exhibit spontaneous DSBs in heterochromatin, and it was proposed that this damage is due to defective DNA replication (2,29,30). Mice lacking Lysine (K) Methyltransferase 1A (KMT1A) (SUV39H1) and KMT1B (SUV39H2) exhibit genome instability and high rates of lymphoma development (31,32), and both KMT1 enzymes and HP1 proteins have been implicated in DNA repair in animals (33)(34)(35)(36)(37)(38)(39)(40)(41)(42). These and other studies suggest that heterochromatin components have important roles during both DNA replication and DNA repair, but the heterochromatin-dependent mechanisms that maintain genome integrity remain poorly defined.…”

Section: Significancementioning

confidence: 99%

Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth

Basenko

Sasaki

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

H3K9 methylation directs heterochromatin formation by recruiting multiple heterochromatin protein 1 (HP1)-containing complexes that deacetylate histones and methylate cytosine bases in DNA. In Neurospora crassa, a single H3K9 methyltransferase complex, called the DIM-5,-7,-9, CUL4, DDB1 Complex (DCDC), is required for normal growth and development. DCDC-deficient mutants are hypersensitive to the genotoxic agent methyl methanesulfonate (MMS), but the molecular basis of genotoxic stress is unclear. We found that both the MMS sensitivity and growth phenotypes of DCDC-deficient strains are suppressed by mutation of embryonic ectoderm development or Su-(var)3-9; E(z); Trithorax (set)-7, encoding components of the H3K27 methyltransferase Polycomb repressive complex-2 (PRC2). Trimethylated histone H3K27 (H3K27me3) undergoes genome-wide redistribution to constitutive heterochromatin in DCDC- or HP1-deficient mutants, and introduction of an H3K27 missense mutation is sufficient to rescue phenotypes of DCDC-deficient strains. Accumulation of H3K27me3 in heterochromatin does not compensate for silencing; rather, strains deficient for both DCDC and PRC2 exhibit synthetic sensitivity to the topoisomerase I inhibitor Camptothecin and accumulate γH2A at heterochromatin. Together, these data suggest that PRC2 modulates the response to genotoxic stress.

show abstract

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

Cited by 55 publications

References 40 publications

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

Intrabody-mediated diverting of HP1β to the cytoplasm induces co-aggregation of H3–H4 histones and lamin-B receptor

Nuclear compartmentalization of DNA repair

Genome-wide redistribution of H3K27me3 is linked to genotoxic stress and defective growth

Contact Info

Product

Resources

About