July 2018 | Iúil 2018

Genome instability is a consequence of transcription deficiency in patients with bone marrow failure

Fri, 20 July 18 14:14

A team of international researchers, including Professor Owen Smith (UCD Professor of Paediatric and Adolescent Haematology) have demonstrated that genome instability in bone marrow failure patients with biallelic ERCC6L2 variants arises due to a particular genetic mutation causing a primary transcription deficiency rather than as a consequence of a DNA repair defect.

Bone marrow failure is an inherited life-threatening condition characterised by defective blood cell formation, developmental abnormalities and predisposition to cancer. Individuals affected by inherited bone marrow failure syndromes present with a variety of hematological complications. These complications include myelodysplastic syndrome and acute myeloid leukemia.

Bone marrow failure caused by biallelic variants in the ERCC excision repair 6 like 2 gene (ERCC6L2) is considered to be a genome instability syndrome with DNA repair compromised in cells. The data from this study indicates a mechanism in bone marrow failure in which patients with ERCC6L2 mutations are defective in the repair of transcription-associated DNA damage.

Researchers have shown that patient-derived lymphoblastoid cell lines exhibit hypersensitivity to DNA damaging agents that specifically activate the transcription coupled nucleotide excision repair (TCNER) pathway. These patients’ cell lines are also hypersensitive to transcription inhibitors that interfere with RNA polymerase II. These patient cell lines are compromised in DNA repair capacity, display abnormal delay in RNA synthesis recovery rates, and fail to accurately stall transcription elongation following treatment with a transcription inhibitor.

The researchers have demonstrated that ERCC6L2 contributes to the DNA damage response through its interaction with an enzyme called DNA-dependent protein kinase (DNA-PK) and that it occupies gene bodies alongside RNA polymerase II. They also observed an increase in nucleoplasmic R-loop density, which could be the cause of the genomic instability.

DNA-PK was initially identified as a regulatory component of transcriptionally poised RNA polymerase II. As transcription is a fundamental mechanism behind cell fate, the role of DNA-PK in regulating this process may have critical implications in bone marrow failure.

This research suggests that the interaction between ERCC6L2 and DNA-PK could be particularly relevant in the repair of transcription-associated DNA lesions.  These findings support the notion of a primary transcription defect rather than a DNA repair defect in patients with BMF caused by the ERCC6L2 genetic mutation.

Original Article

Genome instability is a consequence of transcription deficiency in patients with bone marrow failure harboring biallelicERCC6L2 variants.

Tummala H, Dokal AD, Walne A, Ellison A, Cardoso S, Amirthasigamanipillai S, Kirwan M, Browne I, Sidhu JK, Rajeeve V, Rio-Machin A, Seraihi AA, Duncombe AS, Jenner M, Smith OP, Enright H, Norton A, Aksu T, Özbek NY, Pontikos N, Cutillas P, Dokal I, Vulliamy T.

Proc Natl Acad Sci U S A. 2018 Jul 9. pii: 201803275. doi: 10.1073/pnas.1803275115. PMID:29987015