Warsaw Breakage Syndrome, a Cohesinopathy Associated with Mutations in the XPD Helicase Family Member DDX11/ChlR1

Abstract

The iron-sulfur-containing DNA helicases XPD, FANCJ, DDX11, and RTEL represent a small subclass of superfamily 2 helicases. XPD and FANCJ have been connected to the genetic instability syndromes xeroderma pigmentosum and Fanconi anemia. Here, we report a human individual with biallelic mutations in DDX11. Defective DDX11 is associated with a unique cellular phenotype in which features of Fanconi anemia (drug-induced chromosomal breakage) and Roberts syndrome (sister chromatid cohesion defects) coexist. The DDX11-deficient patient represents another cohesinopathy, besides Cornelia de Lange syndrome and Roberts syndrome, and shows that DDX11 functions at the interface between DNA repair and sister chromatid cohesion.

Global transcriptional disturbances underlie Cornelia de Lange syndrome and related phenotypes

“…Evidence suggests that NIPBL, SMC1A, SMC3, RAD21, and HDAC8, the 5 genes associated with cohesin and CdLS, are each involved in transcriptional regulation (11)(12)(13)(14)(15)(16)(17). Variant alleles in genes encoding proteins important to cohesion function are also associated with other syndromes sharing phenotypic features with CdLS, such as Roberts-SC phocomelia syndrome (MIM # 268300, MIM # 269000) (18) and Warsaw breakage syndrome (MIM # 613398) (19). Due to the extensive clinical heterogeneity and imperfect genotype-phenotype correlations, it is important to investigate the genetic heterogeneity underlying CdLS and CdLS-like phenotypes and to enrich our understanding of the phenotypic spectrum caused by the corresponding gene mutations, i.e., phenotypic expansion.…”

Inherited mutations in the helicase RTEL1 cause telomere dysfunction and Hoyeraal–Hreidarsson syndrome

“…RTEL1 is an essential DNA helicase that belongs to a small family of iron-sulfurcontaining DNA helicases, together with XPD, FANCJ, and DDX11/ChlR1. Mutations in the latter three cause the genome instability diseases Xeroderma pigmentosum, Fanconi anemia, and Warsaw breakage syndrome, respectively (10,11). Rtel1 was originally identified as a dominant regulator of telomere length in mice (12).…”

Timeless functions independently of the Tim-Tipin complex to promote sister chromatid cohesion in normal human fibroblasts

“…These proteins include AND-1, 18,19 which has similarities to Tim-Tipin, including interaction with replicative DNA polymerases and promotion of normal DNA synthesis, 40 and ChlR1, 9 a helicase involved in lagging strand maturation, 41 that is associated with Warsaw breakage syndrome, a cohesinopathy. 24 During the course of DNA replication, replisomes are remodeled when polymerization is stalled or blocked by exogenous and endogenous challenges. Fork uncoupling, translesion synthesis, template switching and fork reversal are examples of replisome remodeling.…”

“…The loading of cohesin onto chromatin, the establishment of SCC and the maintenance and dissolution of cohesion are cell cycle-regulated processes. 23 Defective SCC is associated with developmental genetic disorders, including Roberts syndrome, Cordelia de Lange syndrome and Warsaw breakage syndrome, 24,25 and mutations in SCC genes have been detected in cancers. 26 Large-scale genetic screens in yeast have revealed an intricate network of interactions among DNA replication, checkpoint activation and SCC.…”