**8. Functions of miRNAs in non-homologous end-joining (NHEJ)**

NHEJ is a relatively simple but error prone DNA double strand break repair. It ligates broken ends, without the need for a homologous template. DNA protein kinase (DNA-PK)

In addition, high expression of miR-155 was inversely correlated with the low expression of MLH1 and MSH2 protein in human colorectal cancer. More importantly, human tumors with unexplained MMR inactivation showed miR-155 over expression (Valeri et al., 2010b; Volinia et al., 2006). These results indicate that increased expression of miR-155 down-

miR-504 and miR-125b directly bind to the P53 3'-UTR and down-regulate P53 activity. miR-34a positively up-regulates P53 through SIRT1 inhibition, a negative regulator of P53. miR-29 down-regulates the P85a regulatory subunit of PI3K, which enhances P53 activity

NER recognizes bulky, helix distorting defects, such as cross-linking thymine dimmers. NER is particularly important for removing the vast majority of UV-induced DNA damage. Currently, only one miRNA is reported to be related with NER (Crosby et al., 2009). miR-373 suppresses the expression of a NER protein called RAD23B. RAD23B is a key component of the XPC/RAD23B complex that mediates damage recognition in the NER pathway (Batty et al., 2000). NER activity is functionally reduced in hypoxic cells (Yuan et al., 2000). A possible mechanism for the hpoxia-induced down-regulation of RAD23B is that hpoxia can upregulate miR-373 expression, and the up-regulated miR-373 then suppresses RAD23B expression. This mechanism was supported by the fact that pre-treating cells with anti-miR-373 reversed the hypoxia-mediated down-regulation of RAD23B in hypoxic cells (Crosby,

NHEJ is a relatively simple but error prone DNA double strand break repair. It ligates broken ends, without the need for a homologous template. DNA protein kinase (DNA-PK)

regulates MMR genes and results in an increase in genomic instability.

Fig. 3. miRNA indirectly regulates DNA repair through P53

et al., 2009).

through the negative feedback loop between PI3K-AKT-MDM2 and P53.

**7. Functions of miRNAs in nucleotide excision repair (NER)** 

**8. Functions of miRNAs in non-homologous end-joining (NHEJ)** 

is a core component of mammalian NHEJ and involves a catalytic subunit (DNA-PKcs) that can act as a regulatory element. DNA-PKcs is a molecular sensor for DNA damage that enhances the signal via phosphorylation of many downstream targets. Therefore, DNA-PKcs is an essential factor for NHEJ. Yan et al. found that miR-101 could efficiently target DNA-PKcs and ATM via binding to their 3'- UTRs. Up-regulating miR-101 efficiently reduced the protein levels of DNA-PKcs and ATM in tumor cells, and most importantly, sensitized the tumor cells to radiation in vitro and in vivo (Yan et al., 2010). Radiotherapy kills tumor-cells by inducing DNA double strand breaks (DSBs). However, the efficient repair of double strand breaks in tumors frequently prevents successful treatment. Therefore, miR-101 could be used to target DNA DSB repair genes, in order to sensitize tumors to radiation and improve tumor radiotherapy.
