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Loss of ZBTB24 impa...
Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
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Helfricht, A (author)
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Thijssen, PE (author)
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Rother, MB (author)
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Shah, RG (author)
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- Du, LK (author)
- Karolinska Institutet
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Takada, S (author)
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Rogier, M (author)
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Moritz, J (author)
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IJspeert, H (author)
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Stoepker, C (author)
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van Ostaijen-ten Dam, MM (author)
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Heyer, V (author)
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Luijsterburg, MS (author)
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de Groot, A (author)
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Jak, R (author)
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Grootaers, G (author)
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Wang, J (author)
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Rao, P (author)
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Vertegaal, ACO (author)
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van Tol, MJD (author)
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- Pan-Hammarstrom, Q (author)
- Karolinska Institutet
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Reina-San-Martin, B (author)
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Shah, GM (author)
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van der Burg, M (author)
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van der Maarel, SM (author)
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van Attikum, H (author)
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(creator_code:org_t)
- 2020-08-31
- 2020
- English.
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In: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 217:11
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http://kipublication...
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https://doi.org/10.1...
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Abstract
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- 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.
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- art (subject category)
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- By the author/editor
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Helfricht, A
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Thijssen, PE
-
Rother, MB
-
Shah, RG
-
Du, LK
-
Takada, S
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show more...
-
Rogier, M
-
Moritz, J
-
IJspeert, H
-
Stoepker, C
-
van Ostaijen-ten ...
-
Heyer, V
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Luijsterburg, MS
-
de Groot, A
-
Jak, R
-
Grootaers, G
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Wang, J
-
Rao, P
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Vertegaal, ACO
-
van Tol, MJD
-
Pan-Hammarstrom, ...
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Reina-San-Martin ...
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Shah, GM
-
van der Burg, M
-
van der Maarel, ...
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van Attikum, H
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show less...
- Articles in the publication
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The Journal of e ...
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Karolinska Institutet