Background: Dysregulation of miRNAs is associated with breast cancer. Results: MiR-9 overexpression and transcriptome analysis reveals novel miR-9 targets, including MTHFD2, which can recapitulate anti-proliferative effects of miR-9 overexpression. Conclusion: MiR-9 displays tumor suppressor-like activity in breast cancer cells; MTHFD2 contributes to this activity. Significance: Understanding miR-9-directed regulation of the breast cancer transcriptome is important for diagnosis and therapeutics.

The single-stranded DNA binding proteins (SSBs) are required to maintain the integrity of the genome in all organisms. Replication protein A (RPA) is a nuclear SSB protein found in all eukaryotes and is required for multiple processes in DNA metabolism such as DNA replication, DNA repair, DNA recombination, telomere maintenance and DNA damage signalling. RPA is a heterotrimeric complex, binds ssDNA with high affinity, and interacts specifically with multiple proteins to fulfil its function in eukaryotes. RPA is phosphorylated in a cell cycle and DNA damage-dependent manner with evidence suggesting that phosphorylation has an important function in modulating the cellular DNA damage response. Considering the DNA-binding properties of RPA a mechanism of "molecular counting" to initiate DNA damage-dependent signalling is discussed. Recently a human homologue to the RPA2 subunit, called RPA4, was discovered and RPA4 can substitute for RPA2 in the RPA complex resulting in an "alternative" RPA (aRPA), which can bind to ssDNA with similar affinity as canonical RPA. Additional human SSBs, hSSB1 and hSSB2, were recently identified, with hSSB1 being localized in the nucleus and having implications in DNA repair. Mitochondrial SSBs (mtSSBs) have been found in all eukaryotes studied. mtSSBs are related to prokaryotic SSBs and essential to main the genome stability in eukaryotic mitochondria. Recently human mtSSB was identified as a novel binding partner of p53 and that it is able to stimulate the intrinsic exonuclease activity of p53. These findings and recent results associated with mutations in RPA suggest a link of SSBs to cancer.

Poly(ADP-ribosyl)ation is involved in numerous bio-logical processes including DNA repair, transcription and cell death. Cellular levels of poly(ADP-ribose) (PAR) are regulated by PAR polymerases (PARPs) and the degrading enzyme PAR glycohydrolase (PARG), controlling the cell fate decision between life and death in response to DNA damage. Replication stress is a source of DNA damage, leading to transient stalling of replication forks or to their collapse followed by the generation of double-strand breaks (DSB). The involvement of PARP-1 in replicative stress response has been described, whereas the consequences of a deregulated PAR catabolism are not yet well established. Here, we show that PARG-deprived cells showed an enhanced sensitivity to the replication inhibitor hydroxyurea. PARG is dispensable to recover from transient replicative stress but is necessary to avoid massive PAR production upon prolonged replicative stress, conditions leading to fork collapse and DSB. Extensive PAR accumulation impairs replication protein A association with collapsed forks resulting in compromised DSB repair via homologous recombination. Our results highlight the critical role of PARG in tightly controlling PAR levels produced upon genotoxic stress to prevent the detrimental effects of PAR over-accumulation.

Background: Epigenetic silencing of the RAS association domain family 1A (RASSF1A) tumor suppressor gene promoter has been demonstrated in renal cell carcinoma (RCC) as a result of promoter hypermethylation. Contradictory results have been reported for RASSF1A methylation in normal kidney, thus it is not clear whether a significant difference between RASSF1A methylation in normal and tumor cells of the kidney exists. Moreover, RASSF1A expression has not been characterized in tumors or normal tissue as yet.