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

Tummala, Hemanth; Dokal, Arran; Walne, Amanda J.; Ellison, Alicia; Cardoso, Shirleny; Amirthasigamanipillai, Saranha; Kirwan, Michael; Browne, Isobel; Sidhu, Jasmin; Rajeeve, Vinothini; Río-Machín, Ana; Seraihi, Ahad Al; Duncombe, Andrew; Jenner, Matthew; Smith, Owen; Enright, Helen; Norton, Alice; Aksu, Tekin; Özbek, Namık; Pontikos, Nikolas; Cutillas, Pedro R.; Dokal, Inderjeet; Vulliamy, Tom

doi:10.1073/pnas.1803275115

Cited by 40 publications

(39 citation statements)

References 38 publications

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“…S5a, b ). This has been previously observed by Immunoprecipitation-Mass Spectrometry (IP-MS) analysis, 35 although we cannot conclude whether it is a direct or indirect interaction. Interestingly, consistent with IP-MS analysis and genome-wide yeast two-hybrid report, 11 , 36 we observed a DNA-independent interaction between ERCC6L2 and MRI/CYREN (Fig.…”

Section: Resultsmentioning

confidence: 47%

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

Liu

Shang

et al. 2020

Cell Res

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Programmed DNA recombination in mammalian cells occurs predominantly in a directional manner. While random DNA breaks are typically repaired both by deletion and by inversion at approximately equal proportions, V(D)J and class switch recombination (CSR) of immunoglobulin heavy chain gene overwhelmingly delete intervening sequences to yield productive rearrangement. What factors channel chromatin breaks to deletional CSR in lymphocytes is unknown. Integrating CRISPR knockout and chemical perturbation screening we here identify the Snf2-family helicase-like ERCC6L2 as one such factor. We show that ERCC6L2 promotes double-strand break end-joining and facilitates optimal CSR in mice. At the cellular levels, ERCC6L2 rapidly engages in DNA repair through its C-terminal domains. Mechanistically, ERCC6L2 interacts with other end-joining factors and plays a functionally redundant role with the XLF end-joining factor in V(D)J recombination. Strikingly, ERCC6L2 controls orientation-specific joining of broken ends during CSR, which relies on its helicase activity. Thus, ERCC6L2 facilitates programmed recombination through directional repair of distant breaks.

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Section: Resultsmentioning

confidence: 47%

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

Liu

Shang

et al. 2020

Cell Res

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“…1; Supplementary Fig. 1; Supplementary Data 2), 32 have been reported as part of previously published studies 9,13,14,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] . The additional 17 families ( Fig.…”

Section: Resultsmentioning

confidence: 96%

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

et al. 2020

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The inclusion of familial myeloid malignancies as a separate disease entity in the revised WHO classification has renewed efforts to improve the recognition and management of this group of at risk individuals. Here we report a cohort of 86 acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) families with 49 harboring germline variants in 16 previously defined loci (57%). Whole exome sequencing in a further 37 uncharacterized families (43%) allowed us to rationalize 65 new candidate loci, including genes mutated in rare hematological syndromes (ADA, GP6, IL17RA, PRF1 and SEC23B), reported in prior MDS/AML or inherited bone marrow failure series (DNAH9, NAPRT1 and SH2B3) or variants at novel loci (DHX34) that appear specific to inherited forms of myeloid malignancies. Altogether, our series of MDS/AML families offer novel insights into the etiology of myeloid malignancies and provide a framework to prioritize variants for inclusion into routine diagnostics and patient management.

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“…Nearly a decade ago the first classical inherited bone marrow failure (BMF) syndrome predisposing to myeloid neoplasms (MN) had been reported by the paediatrician Guido Fanconi, and later named Fanconi Anemia (FA) [ 1 ]. Since then, a number of additional inherited BMF syndromes with risk for the development of myelodysplastic syndrome (MDS) and leukemia have been discovered, including severe congenital neutropenia (SCN), Shwachman Diamond syndrome (SDS), telomere biology disorders/dyskeratosis congenita, Down syndrome, RASopathies, and DNA repair disorders [ [2] , [3] , [4] , [5] , [6] , [7] , [8] , [9] , [10] ]. These syndromes are usually straightforward to diagnose because of preexisting syndromic features and haematological symptoms arising from abnormalities of hematopoietic stem and progenitor cells.…”

Section: Introduction: Germline Predisposition In Myeloid Neoplasmsmentioning

confidence: 99%

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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Increasing awareness about germline predisposition and the widespread application of unbiased whole exome sequencing contributed to the discovery of new clinical entities with high risk for the development of haematopoietic malignancies. The revised 2016 WHO classification introduced a novel category of “myeloid neoplasms with germline predisposition” with GATA2 , CEBPA , DDX41 , RUNX1 , ANKRD26 , and ETV6 genes expanding the spectrum of hereditary myeloid neoplasms (MN). Since then, more germline causes of MN were identified, including SAMD9 , SAMD9L , and ERCC6L2 . This review describes the genetic and clinical spectrum of predisposition to MN. The main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders. Combined, GATA2 and SAMD9/SAMD9L (SAMD9/9L) syndromes are recognized as most frequent causes of primary pediatric myelodysplastic syndromes, particularly in setting of monosomy 7. To date, ∼550 cases with germline GATA2 mutations, and ∼130 patients with SAMD9/9L mutations had been reported in literature. GATA2 deficiency is a highly penetrant disorder with a progressive course that often rapidly necessitates bone marrow transplantation. In contrast, SAMD9/SAMD9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.

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

Cited by 40 publications

References 38 publications

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

ERCC6L2 promotes DNA orientation-specific recombination in mammalian cells

The complex genetic landscape of familial MDS and AML reveals pathogenic germline variants

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

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