Rothmund-Thomson syndrome (RTS; also known as poikiloderma congenitale) is a rare, autosomal recessive genetic disorder characterized by abnormalities in skin and skeleton, juvenile cataracts, premature ageing and a predisposition to neoplasia. Cytogenetic studies indicate that cells from affected patients show genomic instability often associated with chromosomal rearrangements causing an acquired somatic mosaicism. The gene(s) responsible for RTS remains unknown. The genes responsible for Werner and Bloom syndromes (WRN and BLM, respectively) have been identified as homologues of Escherichia coli RecQ, which encodes a DNA helicase that unwinds double-stranded DNA into single-stranded DNAs. Other eukaryotic homologues thus far identified are human RECQL, Saccharomyces cerevisiae SGS1 and Schizosaccharomyces pombe rqh1. We recently cloned two new human helicase genes, RECQL4 at 8q24.3 and RECQL5 at 17q25, which encode members of the RecQ helicase family. Here, we report that three RTS patients carried two types of compound heterozygous mutations in RECQL4. The fact that the mutated alleles were inherited from the parents in one affected family and were not found in ethnically matched controls suggests that mutation of RECQL4 at human chromosome 8q24.3 is responsible for at least some cases of RTS.

Bloom's syndrome (BS) and Werner's syndrome (WS) are genetic disorders in which an increased rate of chromosomal aberration is detected. The genes responsible for these diseases, BLM and WRN, have been found to be homologs of Escherichia coli recQ and Saccharomyces cerevisiae SGS1 genes. Here we show that yeast Sgs1 helicase acts as a suppressor of illegitimate recombination through homologous recombination and that human BLM and WRN helicases can suppress the increased homologous and illegitimate recombinations in the S. cerevisiae sgs1 mutant. The results imply a role of BLM and WRN helicases to control genomic stability in human cells. Similar to Sgs1 helicase, BLM helicase suppressed the cell growth in the top3 sgs1 mutation background and restored the increased sensitivity of the sgs1 mutant to hydroxyurea, but the WRN helicase did not. We discussed differential roles of BLM and WRN helicases in human cells. BLM-and WRN-bearing yeasts provide new useful models to investigate human BS and WS diseases.Bloom's syndrome (BS) is an autosomal recessive disorder causing short stature, immunodeficiency, and an increasing risk of cancer. BS cells have a high level of genomic instability at the cellular level, as shown by an increased rate of sister chromatid exchange and chromosomal aberration (1). Werner's syndrome (WS) also is a rare genetic disorder and is characterized by the premature appearance of normal aging in young adults. Cultured cells derived from patients with WS show an increased rate of somatic mutations, chromosome losses, and deletions (2-4). These experiments may suggest an increased rate of illegitimate recombination in both BS and WS cells. Recently, the genes BLM and WRN, responsible for BS and WS, respectively, have been found to be homologs of Escherichia coli recQ and Saccharomyces cerevisiae SGS1 genes, which encode DNA helicases (5-9). In E. coli, RecQ helicase is involved in homologous and illegitimate recombination (7, 10). In yeast, Sgs1 protein physically interacts with topoisomerase II and III (11,12). The mutation of the SGS1 gene suppresses the growth defect generated by top3 mutation and also shows an increased recombination at the repeated ribosomal DNA locus and other loci (9, 12). The sgs1 mutation also reduces the average lifespan of yeast cells while it enhances relocalization of Sir proteins to nucleolus and accumulation of extrachromosomal rDNA circles (13,14). But whether the sgs1 mutation affects illegitimate recombination is unknown.Illegitimate recombination takes place between nonhomologous DNA sequences or very short regions of homology. Nonhomologous end-joining, which is known to be mediated by Rad50, Xrs2, Mre11, Hdf1, Ku80, and Dnl4 as well as silencing factors Sir2, Sir3,, has an essential role in illegitimate recombination. In this paper, we show that yeast Sgs1 helicase acts as a suppressor of illegitimate recombination through homologous recombination and that human BLM and WRN helicases can suppress the increased homologous and illegitimate recombinati...

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