Phf5a regulates DNA repair in class switch recombination via p400 and histone H2A variant deposition

Abstract

Antibody class switch recombination (CSR) is a locus-specific genomic rearrangement mediated by switch (S) region transcription, activation-induced cytidine deaminase (AID)-induced DNA breaks, and their resolution by non-homologous end joining (NHEJ)-mediated DNA repair. Due to the complex nature of the recombination process, numerous cofactors are intimately involved, making it important to identify rate-limiting factors that impact on DNA breaking and/or repair. Using an siRNA-based loss-of-function screen of genes predicted to encode PHD zinc-finger-motif proteins, we identify the splicing factor Phf5a/Sf3b14b as a novel modulator of the DNA repair step of CSR. Loss of Phf5a severely impairs AID-induced recombination, but does not perturb DNA breaks and somatic hypermutation. Phf5a regulates NHEJ-dependent DNA repair by preserving chromatin integrity to elicit optimal DNA damage response and subsequent recruitment of NHEJ factors at the S region. Phf5a stabilizes the p400 histone chaperone complex at the locus, which in turn promotes deposition of H2A variant such as H2AX and H2A.Z that are critical for the early DNA damage response and NHEJ, respectively. Depletion of Phf5a or p400 blocks the repair of both AID-and I-SceI-induced DNA double-strand breaks, supporting an important contribution of this axis to programmed as well as aberrant recombination.

The H2A.Z-KDM1A complex promotes tumorigenesis by localizing in the nucleus to promote SFRP1 promoter methylation in cholangiocarcinoma cells

“…Some previous studies have demonstrated that H2A.Z was shown to interact with components of complexes involved in a multitude of biological processes, such as DNA damage repair [ 26 ], gene activation [ 27 ], gene repression [ 28 ], various transcription factors [ 29 – 31 ], and chromatin remodeling [ 32 ]; however, the underlying mechanism of action remains unclear in ICC. Using the STRING database, we identified potential molecules that interact with H2A.Z (Fig.…”

“…4 A and Fig. S 2 A show, the downregulation of HP1α can decrease H3K9me3 enrichment and the DNA methylation rate in the P1 region (-116 ~ + 1 bp) of the SFRP1 promoter, resulting in the increase of SFRP1 expression [ 26 ]. In order to explore whether H2A.Z, similar to HP1α, affects SFRP1 expression by influencing the histone methylation level and DNA methylation rate of the SFRP1 promoter.…”

XLID Syndrome Gene Med12 Promotes Ig Isotype Switching through Chromatin Modification and Enhancer RNA regulation

“…How AID regulates the mechanistically distinct processes of S region DNA double strand breaks and S-S synapse formation remains poorly understood (69). While numerous AID-interacting and non-interacting CSR regulatory factors have been identified, these factors appear to play exclusive roles in either DNA break, repair, or synapse formation (4,(70)(71)(72)(73)(74). Here, we show Med12 is a novel CSR cofactor that not only promotes AID-induced DNA double strand breaks and synapse formation but also supports DNA repair via NHEJ (Fig.…”

Medical image encryption algorithm based on a new five-dimensional three-leaf chaotic system and genetic operation

“…DNA recombination [ 37 – 39 ] refers to the recombination of DNA fragments from different sources to disrupt the original DNA sequence. For example, the two DNA double strands intercept a 4-base DNA fragment at the end, and recombine the two DNA fragments with the original DNA strand to obtain two DNA strands that are different from the original.…”

“…DNA recombination technology [ 37 – 39 ] refers to the use of artificial means to recombine DNA fragments with a certain special meaning from different sources to achieve the purpose of changing biological characteristics. In this paper, DNA recombination technology is introduced into DNA encryption, and arbitrary fragments are changed by artificial means.…”