Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome.
Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome.
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DOI：
10.1007/s00018-014-1569-4
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发表时间：
2014-07
期刊：
影响因子：
--
通讯作者：
Brosh RM Jr
中科院分区：
文献类型：
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作者：
Bharti SK;Khan I;Banerjee T;Sommers JA;Wu Y;Brosh RM Jr
2010年，一种新的隐性粘连蛋白病被描述为华沙断裂综合征（WABS）。患有WABS的个体表现为小头畸形、产前和产后生长迟缓和异常皮肤色素沉着。细胞遗传学分析显示丝裂霉素C（MMC）诱导的染色体断裂，然而，一个额外的姐妹染色单体凝聚缺陷也被观察到。WABS在遗传上与ChlR 1/DDX 11基因中的双等位基因突变相关，该基因编码铁-硫（Fe-S）簇DNA解旋酶的保守家族的蛋白质。已知ChlR 1的芽殖酵母直系同源物（称为Chl 1）中的突变会导致姐妹染色单体凝聚缺陷，表明该基因具有保守的功能。2012年，三名受影响的兄弟姐妹被确定为与原始WABS病例相似的症状，并发现ChlR 1保守的Fe-S结构域中存在纯合突变，证实了遗传连锁。值得注意的是，临床相关的突变扰乱ChlR 1 DNA解旋活性。除了其在人类疾病中的遗传重要性之外，ChlRl还涉及乳头瘤病毒基因组维持和癌症。虽然它在基因组稳态中的精确功能仍然没有很好地理解，但正在进行的ChlR 1分子研究表明，解旋酶在细胞复制和/或DNA修复中起着至关重要的作用。
In 2010, a new recessive cohesinopathy disorder, designated Warsaw breakage syndrome (WABS), was described. The individual with WABS displayed microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Cytogenetic analysis revealed mitomycin C (MMC)-induced chromosomal breakage; however, an additional sister chromatid cohesion defect was also observed. WABS is genetically linked to bi-allelic mutations in the ChlR1/DDX11 gene which encodes a protein of the conserved family of Iron–Sulfur (Fe–S) cluster DNA helicases. Mutations in the budding yeast ortholog of ChlR1, known as Chl1, were known to cause sister chromatid cohesion defects, indicating a conserved function of the gene. In 2012, three affected siblings were identified with similar symptoms to the original WABS case, and found to have a homozygous mutation in the conserved Fe–S domain of ChlR1, confirming the genetic linkage. Significantly, the clinically relevant mutations perturbed ChlR1 DNA unwinding activity. In addition to its genetic importance in human disease, ChlR1 is implicated in papillomavirus genome maintenance and cancer. Although its precise functions in genome homeostasis are still not well understood, ongoing molecular studies of ChlR1 suggest the helicase plays a critically important role in cellular replication and/or DNA repair.