Initiation of DNA Replication Requires the RECQL4 Protein Mutated in Rothmund-Thomson Syndrome

Abstract

How the replication machinery is loaded at origins of DNA replication is poorly understood. Here, we implicate in this process the Xenopus laevis homolog (xRTS) of the RECQL4 helicase mutated in Rothmund-Thomson syndrome. xRTS, which bears homology to the yeast replication factors Sld2/DRC1, is essential for DNA replication in egg extracts. xRTS can be replaced in extracts by its human homolog, while RECQL4 depletion from mammalian cells induces proliferation failure, suggesting an evolutionarily conserved function. xRTS accumulates on chromatin during replication initiation, after prereplication-complex (pre-RC) proteins, Cut5, Sld5, or Cdc45 but before replicative polymerases. xRTS depletion suppresses the loading of RPA, the ssDNA binding protein that marks unwound origins before polymerase recruitment. However, xRTS is unaffected by xRPA depletion. Thus, xRTS functions after pre-RC formation to promote loading of replication factors at origins, a previously unrecognized activity necessary for initiation. This role connects defective replication initiation to a chromosome-fragility disorder.

DNA replication is altered in Immunodeficiency Centromeric instability Facial anomalies (ICF) cells carrying DNMT3B mutations

“…5 Chromosome instability in ICF syndrome has always been associated with hypomethylation of the involved chromosomal regions. 27 However, it is tempting to suggest that altered DNA replication may also contribute to the genomic instability that characterizes ICF cells, similar to what is observed in other pathological conditions (ie, cancer, 28 Bloom syndrome, 29 Rothmund-Thomson syndrome 30 ) where the alteration of the replication process is associated with a high level of spontaneously occurring and/or induced chromosome abnormalities.…”

Kaposi's Sarcoma-Associated Herpesvirus ori - Lyt -Dependent DNA Replication: Involvement of Host Cellular Factors

“…Although KSHV encodes a heterotrimeric helicase-primase complex, the complex is conserved among all herpesviruses and believed to unwind duplex viral DNA at replication forks and to prime lagging strand synthesis (12). Recently, cellular RecQL4, another member of the RecQ helicase family, was shown to promote loading of replication factors at origins after prereplication complexes were formed, suggesting that RecQL4 plays a role in unwinding DNA at the replication origin (32). Taken together, the identification of RecQL in the KSHV replication complex raises an exciting hypothesis, that the cellular RecQ helicase may be the long-sought helicase that unwinds origin DNA in the initiation of KSHV and EBV lytic DNA replication.…”

Erratum to: Structure and Mechanisms of SF1 DNA Helicases

“…Many of the biological functions of various helicases are listed in Table 2.1. Helicases are implicated in processes ranging from replication to translation [8,[10][11][12][46][47][48][49] and also in ATPdependent chromatin remodeling [50,51]. Replicative helicases deal with the process of nucleic acid replication (initiation, elongation, and termination).…”

“…By doing so, helicases allow access to the genetic information locked in the duplex DNA. Helicases participate in various aspects of nucleic acid metabolism such as DNA replication, recombination, repair, transcription, translation, and splicing of RNA transcripts [3][4][5][6][7][8][9][10][11][12][13].…”