Altered DNA ligase I activity in Bloom's syndrome cells

Abstract

Cells from patients with Bloom's syndrome, a rare disease associated with increased cancer frequency, exhibit cytological abnormalities. These include increased numbers of homologous chromatid interchange figures and sister-chromatid exchanges, together with abnormally slow replicon-fork progression and retarded rate of DNA-chain maturation, and suggest that the primary defect in this recessive disorder affects S-phase DNA replication. DNA ligases and DNA polymerases have long been prime candidates for abnormality in Bloom's syndrome, but various studies of DNA polymerases in Bloom's syndrome cells have disclosed no abnormalities. Evidence is presented here, as in the accompanying paper from a different laboratory, for the existence in Bloom's syndrome of an abnormality of the DNA ligase involved in semi-conservative DNA replication.

The Fanconi Anemia/BRCA pathway: new faces in the crowd

“…BLM, topoisomerase III, and replication protein A associate with constituents of the FA complex 1 (the BRAFT complex) (Meetei et al 2003b). These proteins have been shown to cooperate in DNA unwinding and have been implicated in the response to replication fork arrest (Chan et al 1987;Brosh Jr. et al 2000;Wu and Hickson 2002). Mutation of BLM in common with other FA genes results in chromosomal breakage (Risinger and Groden 2004), although it is important to note that BLM-deficient cells also exhibit increased SCE, a phenotype not observed in FA cells.…”

Mammalian Dna Ligases

“…Thus , the complete DNA sequence of Epstein-Barr virus (107) (115). However, Bloom's syndrome cells exhibit an apparent DNA ligation deficiency in vitro and in vivo (28,78,79,(115)(116)(117).…”

Mammalian DNA Ligases

“…These data indicate that DNA ligase III may be a heterodimer comprising two subunits, with the active site for enzyme-AMP formation present in the larger subunit. All other DNA ligases investigated to date have a monomeric structure, although dimerization or aggregation of DNA ligase I has been observed under certain conditions (78,79). For this reason, it cannot yet be concluded whether the 46-kDa peptide is an essential and integral part of DNA ligase III, or if it represents a separate protein that binds tenaciously to the 100-kDa DNA ligase component and may be in volved in related cellular functions.…”