PXD014741

PXD014741 is an original dataset announced via ProteomeXchange.

Title	Loss of ZBTB24, a novel non-homologous end-joining protein, impairs class-switch recombination in ICF syndrome
Description	The autosomal recessive immunodeficiency, centromeric instability and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite recent successes in the identification of the underlying gene defects, it is currently unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from ICF2 patients impairs non-homologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and subtype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates auto-poly(ADP-ribosyl)ation of this enzyme. The zinc finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, by binding to poly(ADP-ribose) chains ZBTB24 protects these moieties from degradation by poly(ADP-ribose) glycohydrolase (PARG). This enhances the poly(ADP-ribose)-dependent interaction between PARP1 and the LIG4/XRCC4 NHEJ complex and promotes NHEJ by facilitating the assembly of this repair complex at DNA breaks. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF syndrome.
HostingRepository	PRIDE
AnnounceDate	2020-08-19
AnnouncementXML	Submission_2020-08-19_07:46:59.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Alfred Vertegaal
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	No PTMs are included in the dataset
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-07-24 08:19:05	ID requested
⏵ 1	2020-08-19 07:46:59	announced

Dataset with its publication pending

submitter keyword: Human, ZBTB24, PARP1

Alfred C.O. Vertegaal
contact affiliation	Cell and Chemical Biology Leiden University Medical Center the Netherlands
contact email	vertegaal@lumc.nl
lab head
Alfred Vertegaal
contact affiliation	Leiden University Medical Center
contact email	vertegaal@lumc.nl
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD014741
     1. Label: PRIDE project
     2. Name: Loss of ZBTB24, a novel non-homologous end-joining protein, impairs class-switch recombination in ICF syndrome