Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome.
Animals
B-Lymphocytes
/ immunology
DNA Breaks
DNA End-Joining Repair
/ genetics
Face
/ abnormalities
HEK293 Cells
Humans
Immunoglobulin Class Switching
/ genetics
Immunoglobulin Switch Region
Mice
Mutation
Poly (ADP-Ribose) Polymerase-1
/ metabolism
Primary Immunodeficiency Diseases
/ blood
Repressor Proteins
/ genetics
Transcription Factors
/ genetics
Transfection
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
02 11 2020
02 11 2020
Historique:
received:
09
09
2019
revised:
06
04
2020
accepted:
19
05
2020
entrez:
1
9
2020
pubmed:
1
9
2020
medline:
11
3
2021
Statut:
ppublish
Résumé
The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is 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 mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.
Identifiants
pubmed: 32865561
pii: 152060
doi: 10.1084/jem.20191688
pmc: PMC7526497
pii:
doi:
Substances chimiques
Repressor Proteins
0
Transcription Factors
0
ZBTB24 protein, human
0
Zbtb24 protein, mouse
0
PARP1 protein, human
EC 2.4.2.30
Parp1 protein, mouse
EC 2.4.2.30
Poly (ADP-Ribose) Polymerase-1
EC 2.4.2.30
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : 242551
Pays : International
Organisme : European Research Council
ID : 310913
Pays : International
Informations de copyright
© 2020 Helfricht et al.
Déclaration de conflit d'intérêts
Disclosure: The authors declare no competing interests exist.
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