The cellular response to DNA breaks is influenced by chromatin compaction. To identify chromatin regulators involved in the DNA damage response, we screened for genes that affect recovery following DNA damage using an RNAi library of chromatin regulators. We identified genes involved in chromatin remodeling, sister chromatid cohesion, and histone acetylation not previously associated with checkpoint recovery. Among these is the PHD finger protein 6 (PHF6), a gene mutated in Börjeson-Forssman-Lehmann syndrome and leukemic cancers. We find that loss of PHF6 dramatically compromises checkpoint recovery in G2 phase cells. Moreover, PHF6 is rapidly recruited to sites of DNA lesions in a PARP-dependent manner and required for efficient DNA repair through classical non-homologous end joining. These results indicate that PHF6 is a novel DNA damage response regulator that promotes end joining-mediated repair, thereby stimulating timely recovery from the G2 checkpoint.
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http://dx.doi.org/10.15252/embr.201948460 | DOI Listing |
Ugeskr Laeger
December 2024
Lever-, Mave- og Tarmsygdomme, Aarhus Universitetshospital.
Immunotherapy-induced hepatitis is a well-known and relatively common side effect of immune checkpoint inhibitors. It is usually mild to moderate and responds well to corticosteroids with a full recovery. However, in rare cases, severe liver injury may develop, leading to fulminant liver failure.
View Article and Find Full Text PDFNat Commun
December 2024
Drug Hypersensitivity Clinical and Research Center, Chang Gung Memorial Hospital, Linkou Branch, Taoyuan, Taiwan.
Immune checkpoint inhibitors (ICI) represent new anticancer agents and have been used worldwide. However, ICI can potentially induce life-threatening severe cutaneous adverse reaction (SCAR), such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), hindering continuous ICI therapy. We examine 6 cohorts including 25 ICI-induced SJS/TEN patients and conduct single-cell RNA sequencing (scRNA-seq) analysis, which shows overexpression of macrophage-derived CXCL10 that recruits CXCR3 cytotoxic T lymphocytes (CTL) in blister cells from ICI-SJS/TEN skin lesions.
View Article and Find Full Text PDFExpert Opin Drug Metab Toxicol
December 2024
Liver Research Center, Beijing Friendship Hospital, Key Laboratory on Translational Medicine on Cirrhosis, National Clinical Research Center for Digestive Disease, Capital Medical University, Beijing, China.
Background: Immune-mediated liver injury caused by immune checkpoint inhibitors (ILICI) and autoimmune hepatitis (AIH) are both related to the distorted immune system. However, ILICI differs from AIH in several distinct ways. We aimed to study the differences between ILICI and AIH.
View Article and Find Full Text PDFPresse Med
December 2024
Division of Pathology, Hôpital Maisonneuve-Rosemont, Université de Montréal, Montréal, Canada.
Introduction: Gastric and gastroesophageal junction adenocarcinoma is a disease with high mortality. Approximately 10% of these tumors are characterized by microsatellite instability with a presumed good response to immunotherapy. So far, treatment with checkpoint inhibitors is part of palliative regimens, in the Czech Republic this treat-ment is reimbursed in patients with MSI-H gastroesophageal adenocarcinoma exhibiting a combined positive score ≥ 5.
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