PXD042199-1

PXD042199 is an original dataset announced via ProteomeXchange.

Title	TOPBP1 Shapes XY Silencing Dynamics Independently of Sex Body Formation to Ensure Male Fertility
Description	In mammals and several other taxa, the ability of males to cope with the limited synapsis of the X and Y chromosomes during prophase I of meiosis relies on the process of meiotic sex chromosome inactivation (MSCI). Components of the somatic DNA damage response machinery, including ATR, TOPBP1, MDC1 and BRCA1 play key roles in MSCI, although how they establish XY silencing remains incompletely understood. In particular, it remains unclear how DDR factors coordinate XY silencing with DNA repair, chromosome synapsis and the formation of the sex body, a distinct phase-separated sub-nuclear structure formed during prophase I to house the unsynapsed XY bivalent. Here we report a mutant mouse (Topbp1B5/B5), harboring mutations in the BRCT5 domain of Topbp1, that shows impaired XY silencing but grossly normal sex body formation. While Topbp1B5/B5 mice are viable, without detectable somatic defects, males are completely infertile. Distinct from mice lacking ATR or TOPBP1 specifically during meiosis, Topbp1B5/B5 males exhibit normal chromosome synapsis and canonical markers of DNA repair in early prophase I. ATR signaling is mostly intact in Topbp1B5/B5 spermatocytes, although specific ATR-dependent events are disrupted, including localization of the RNA:DNA helicase Senataxin to chromatin loops of the XY. Strikingly, while Topbp1B5/B5 spermatocytes are able to initiate MSCI the completion of gene silencing is defective, with a subset of X chromosome genes displaying distinct patterns of transcriptional deregulation. These findings suggest a non-canonical role for the ATR-TOPBP1 signaling axis in XY silencing dynamics at advanced stages in pachynema. This is the first DDR mutant that separates XY silencing from sex body formation, as well as TOPBP1’s role in spermatogenesis from its roles in organismal viability.
HostingRepository	PRIDE
AnnounceDate	2024-02-10
AnnouncementXML	Submission_2024-02-09_17:14:45.840.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Carolline Ascencao
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090; scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue; 6x(13)C labeled residue
Instrument	Q Exactive HF

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-12 17:19:04	ID requested
⏵ 1	2024-02-09 17:14:46	announced
2	2024-10-22 06:29:02	announced	2024-10-22: Updated project metadata.

10.7554/ELIFE.90887.2;

submitter keyword: TOPBP1,Male meiosis, Mice, MSCI and XY silencing

Marcus Smolka
contact affiliation	Cornell University
contact email	mbs266@cornell.edu
lab head
Carolline Ascencao
contact affiliation	Cornell University
contact email	ca447@cornell.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042199
     1. Label: PRIDE project
     2. Name: TOPBP1 Shapes XY Silencing Dynamics Independently of Sex Body Formation to Ensure Male Fertility