Author:
Tummala Hemanth,Dokal Arran D.,Walne Amanda,Ellison Alicia,Cardoso Shirleny,Amirthasigamanipillai Saranha,Kirwan Michael,Browne Isobel,Sidhu Jasmin K.,Rajeeve Vinothini,Rio-Machin Ana,Seraihi Ahad Al,Duncombe Andrew S.,Jenner Matthew,Smith Owen P.,Enright Helen,Norton Alice,Aksu Tekin,Özbek Namık Yaşar,Pontikos Nikolas,Cutillas Pedro,Dokal Inderjeet,Vulliamy Tom
Abstract
Biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) are known to cause bone marrow failure (BMF) due to defects in DNA repair and mitochondrial function. Here, we report on eight cases of BMF from five families harboring biallelic variants in ERCC6L2, two of whom present with myelodysplasia. We confirm that ERCC6L2 patients’ lymphoblastoid cell lines (LCLs) are hypersensitive to DNA-damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. Interestingly, patients’ LCLs are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II (RNA Pol II) and display an abnormal delay in transcription recovery. Using affinity-based mass spectrometry we found that ERCC6L2 interacts with DNA-dependent protein kinase (DNA-PK), a regulatory component of the RNA Pol II transcription complex. Chromatin immunoprecipitation PCR studies revealed ERCC6L2 occupancy on gene bodies along with RNA Pol II and DNA-PK. Patients’ LCLs fail to terminate transcript elongation accurately upon DNA damage and display a significant increase in nuclear DNA–RNA hybrids (R loops). Collectively, we conclude that ERCC6L2 is involved in regulating RNA Pol II-mediated transcription via its interaction with DNA-PK to resolve R loops and minimize transcription-associated genome instability. The inherited BMF syndrome caused by biallelic variants in ERCC6L2 can be considered as a primary transcription deficiency rather than a DNA repair defect.
Funder
Medical Research Council UK
Bloodwise
Publisher
Proceedings of the National Academy of Sciences
Cited by
38 articles.
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