Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

Tummala Hemanth; Dokal Arran D.; Walne AmandaEllison AliciaCardoso ShirlenyAmirthasigamanipillai SaranhaKirwan MichaelBrowne IsobelSidhu Jasmin K.Rajeeve VinothiniRio-Machin AnaAl Seraihi AhadDuncombe Andrew S.Jenner MatthewSmith Owen P.Enright HelenNorton AliceAksu TekinOzbek Namik YasarPontikos NikolasCutillas PedroDokal InderjeetVulliamy Tom

首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America. >Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

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Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

机译：Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

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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 mitochondria! 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.

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《Proceedings of the National Academy of Sciences of the United States of America.》 |2018年第30期|7777-7782|共6页
作者
Tummala Hemanth; Dokal Arran D.; Walne AmandaEllison AliciaCardoso ShirlenyAmirthasigamanipillai SaranhaKirwan MichaelBrowne IsobelSidhu Jasmin K.Rajeeve VinothiniRio-Machin AnaAl Seraihi AhadDuncombe Andrew S.Jenner MatthewSmith Owen P.Enright HelenNorton AliceAksu TekinOzbek Namik YasarPontikos NikolasCutillas PedroDokal InderjeetVulliamy Tom;
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作者单位

Queen Mary Univ London, Blizard Inst, Genom & Child Hlth, London E1 2AT, England;

Queen Mary Univ London, Barts Canc Inst, London EC1M 6BQ, England;

Southampton Univ Hosp, Dept Haematol, Southampton SO16 6YD, Hants, EnglandTrinity Coll Dublin, Our Ladys Childrens Hosp, Dublin 12, IrelandAdelaide & Meath Hosp, Trinity Coll Med Sch, Dublin 24, IrelandBirmingham Childrens Hosp, Dept Clin & Lab Haematol, Birmingham B4 6NH, W Midlands, EnglandUniv Hlth Sci, Ankara Child Hlth & Dis Hematol Oncol Training &, Pediat Hematol & Oncol, TR-06100 Ankara, TurkeyUCL, UCL Inst Ophthalmol, London EC1V 9EL, England;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
ERCC6L2; DNA PK; transcription; DNA repair; R loops;

Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelic ERCC6L2 variants

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