Recombine and Associate to Prevent Genomic Instability and Premature Aging

摘要

To overcome obstacles for DNA replication, a plethora of proteins have to perform tasks, such as recognizing the replication-blocking lesion, unwinding local DNA, removing the blockade, filling the gap by de novo DNA synthesis, and finally, DNA ligation. Surprisingly, human somatic cells contain 5 RecQ 3'-5' helicase genes and 11 genes encoding 3'-5' exonucleases, each sufficient to unwind the DNA and to remove blockades to DNA replication [Shevelev and Hiibscher, 2002; Hickson, 2003; Keijz-ers et al., 2014]. This may suggest that evolution generated genetic and molecular redundancy. If so, loss of any one 3'-5' helicase or 3'-5' exonuclease would be without consequence, for a similar enzyme should be able 'to take over'. However, deficiency for a single 3'-5' helicase or a single 3'-5' exonuclease may result in autosomal recessive disorders, which are characterized by distinct phenotypes but also share some features among each other. Both loss of the BLM- or the RECQL4- encoded helicases in Bloom syndrome (BS) and Rothmund-Thomson syndrome (RTS), respectively, gives rise to short stature, due to reduced growth of the long bones, sun-sensitive skin rash and telangiectasia as well as several other distinct phenotypes. RTS and Werner syndrome (WS) share cataracts, either juvenile in the case of RTS or in adult WS patients.