HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Spruce, Catrina; Dlamini, Sibongakonke; Ananda, Guruprasad; Bronkema, Naomi; Tian, Hui; Paigen, Ken; Carter, Gregory W.; Baker, Christopher L.

doi:10.1101/764183

Cited by 2 publications

(2 citation statements)

References 99 publications

(139 reference statements)

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“…Although it has been suggested that ZCWPW1 might recruit the DSB machinery (M. Spruce et al, 2019), our data imply DSB formation and positioning are largely unaffected by loss of ZCWPW1 and occur at PRDM9bound hotspots. Moreover DMC1, RAD51 and RPA2 loading also appear normal (Figure 7A and (M. Li et al, 2019)), but asynapsis and failure to remove DMC1 imply a profound downstream impact.…”

Section: Discussioncontrasting

confidence: 64%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified.We identified Zcwpw1, which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9. Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons.Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract LegendIn humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

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Section: Discussioncontrasting

confidence: 64%

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

Wells

Bitoun

Moralli

et al. 2019

Preprint

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“…Indeed, DNA methylation in insects is largely associated with gene bodies and not with heterochromatic transposable elements (72)(73)(74)(75), apparently contradicting the suggested specialized role of CDCA7-HELLS in maintaining DNA methylation at heterochromatin. It will be important to test the functional significance of CDCA7-hemimethylated CpG binding in other processes where HELLS and/or CDCA7 play roles, such as DNA repair, resolution of DNA-RNA hybrids, and macroH2A deposition (49,62,(76)(77)(78)(79)(80)(81)(82). Third, the low resolution of our current cryo-EM structure of the CDCA7-nucleosome complex prevented us from dissecting the structural basis for hemimethylated CpG recognition by CDCA7 at atomic resolution.…”

Section: Discussionmentioning

confidence: 99%

CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS

Wassing,

Nishiyama,

Hiruta

et al. 2023

Preprint

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Mutations of the SNF2 family ATPase HELLS and its activator CDCA7 cause immunodeficiency-centromeric instability-facial anomalies (ICF) syndrome, characterized by hypomethylation at heterochromatin. The unique zinc-finger domain, zf-4CXXC_R1, of CDCA7 is widely conserved across eukaryotes but is absent from species that lack HELLS and DNA methyltransferases, implying its specialized relation with methylated DNA. Here we demonstrate that zf-4CXXC_R1 acts as a hemimethylated DNA sensor. The zf-4CXXC_R1 domain of CDCA7 selectively binds to DNA with a hemimethylated CpG, but not unmethylated or fully methylated CpG, and ICF disease mutations eliminated this binding. CDCA7 and HELLS interact via their N-terminal alpha helices, through which HELLS is recruited to hemimethylated DNA. While placement of a hemimethylated CpG within the nucleosome core particle can hinder its recognition by CDCA7, cryo-EM structure analysis of the CDCA7-nucleosome complex suggests that zf-4CXXC_R1 recognizes a hemimethylated CpG in the major groove at linker DNA. Our study provides insights into how the CDCA7-HELLS nucleosome remodeling complex uniquely assists maintenance DNA methylation.

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HELLS and PRDM9 form a Pioneer Complex to Open Chromatin at Meiotic Recombination Hotspots

Cited by 2 publications

References 99 publications

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

ZCWPW1 is recruited to recombination hotspots by PRDM9, and is essential for meiotic double strand break repair

CDCA7 is a hemimethylated DNA adaptor for the nucleosome remodeler HELLS

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