PTIP epigenetically regulates DNA damage-induced cell cycle arrest by upregulating PRDM1.

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 101563288 Publication Model: Electronic Cited Medium: Internet ISSN: 2045-2322 (Electronic) Linking ISSN: 20452322 NLM ISO Abbreviation: Sci Rep Subsets: MEDLINE

Original Publication: London : Nature Publishing Group, copyright 2011-

Cell Cycle Checkpoints* ; DNA Damage* ; DNA-Binding Proteins*/metabolism ; DNA-Binding Proteins*/genetics ; Positive Regulatory Domain I-Binding Factor 1*/metabolism ; Positive Regulatory Domain I-Binding Factor 1*/genetics; Animals ; Humans ; Mice ; Carrier Proteins/metabolism ; Carrier Proteins/genetics ; Epigenesis, Genetic ; Histones/metabolism ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Leukemia, Myeloid, Acute/pathology ; Nuclear Proteins/metabolism ; Nuclear Proteins/genetics ; Radiation, Ionizing ; Up-Regulation

The genome is constantly exposed to DNA damage from endogenous and exogenous sources. Fine modulation of DNA repair, chromatin remodeling, and transcription factors is necessary for protecting genome integrity, but the precise mechanisms are still largely unclear. We found that after ionizing radiation (IR), global trimethylation of histone H3 at lysine 4 (H3K4me3) was decreased at an early (5 min) post-IR phase but increased at an intermediate (180 min) post-IR phase in both human and mouse hematopoietic cells. We demonstrated that PTIP, a component of the MLL histone methyltransferase complex, is required for H3K4me3 upregulation in the intermediate post-IR phase and promotes cell cycle arrest by epigenetically inducing a cell cycle inhibitor, PRDM1. In addition, we found that PTIP expression is specifically downregulated in acute myeloid leukemia patients. These findings collectively suggest that the PTIP-PRDM1 axis plays an essential role in proper DNA damage response and its deregulation contributes to leukemogenesis.
(© 2024. The Author(s).)

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18K16087 JSPS KAKENHI; JP24gm1310006 AMED-CREST

Keywords: DNA damage response; H3K4me3; Histone methylation; PTIP

0 (Carrier Proteins)
0 (DNA-Binding Proteins)
0 (histone H3 trimethyl Lys4)
0 (Histones)
0 (Nuclear Proteins)
0 (Paxip1 protein, mouse)
EC 2.1.1.- (Positive Regulatory Domain I-Binding Factor 1)
0 (PAXIP1 protein, human)
138415-26-6 (PRDM1 protein, human)

Date Created: 20240803 Date Completed: 20240803 Latest Revision: 20240816

20240816

PMC11297997

10.1038/s41598-024-68295-w

39097652