Rapidly dividing cancer cells show elevated levels of DNA double-strand breaks (DSBs) resulting from replication stress and linked to genome instability. To verify the hypothesis that a low level of endogenous replicative DNA damage may impact gene expression programs and cell biology features relevant to cancer progression, we used DNA ligase I (LigI) defective 46BR.1G1 fibroblasts, deriving from a patient who died at 19 for lymphoma, and the 7A3 cell clone, obtained from 46BR.1G1 by stably expressing ectopic wild-type LigI. LigI deficiency impairs maturation of newly synthesized DNA and increases the number of DSBs and γH2AX foci, features associated with genome instability commonly found also in pre-neoplastic lesions. In order to decipher the strategy used to cope with replicative DNA damage, we have compared gene expression profiles in 46BR.1G1 and 7A3 cells. Among the differentially expressed genes, we identified a group of long noncoding RNAs (lncRNAs) which show significant transcriptional alteration in 46BR.1G1 cells, and appear to be relevant for cancer progression. An interesting up-regulated lncRNA in 46BR.1G1 cells is LINP1 (lncRNA in nonhomologous end joining (NHEJ) pathway 1) which has been shown to be involved in DNA repair. We have observed that LINP1 up-regulation contributes to proliferation and survival of 46BR.1G1 that could account for genome instability. Moreover, we observed that LINP1 is upregulated at later times in control human fibroblasts exposed to exogenous sources of DNA damage. Our observations support the notion that LINP1 lncRNA targeting could reduce the DNA repair efficacy of tumour cells.

* These authors contributed equally to this work.