HMGNs, DNA repair and cancer

Abstract

DNA lesions threaten the integrity of the genome and are a major factor in cancer formation and progression. Eukaryotic DNA is organized in nucleosome-based higher order structures, which form the chromatin fiber. In recent years, considerable knowledge has been gained on the importance of chromatin dynamics for the cellular response to DNA damage and for the ability to repair DNA lesions. High Mobility Group N1 (HMGN1) protein is an emerging factor that is important for chromatin alterations in response to DNA damage originated from both ultra violet light (UV) and ionizing irradiation (IR). HMGN1 is a member in the HMGN family of chromatin architectural proteins. HMGNs bind directly to nucleosomes and modulate the structure of the chromatin fiber in a highly dynamic manner. This review focuses mainly on the roles of HMGN1 in the cellular response pathways to different types of DNA lesions and in transcriptional regulation of cancer-related genes. In addition, emerging roles for HMGN5 in cancer progression and for HMGN2 as a potential tool in cancer therapy will be discussed.

Fig. 1

The involvement of HMGN1 in TCR. UV light induces photolesions (marked in red asterisk) within the genome, which can impose a blockage on transcription. Once elongating RNA polymerase encounters a transcription-blocking photolesion its interaction with CSB is stabilized to initialize the TCR pathway. CSB is required for recruitment of additional factors such as p300, CSA, XAB2 and HMGN1 to initiate the repair of the lesion. p300 may acetylate residues within histone tails in the proximate nucleosomes to the lesion to facilitate chromatin de-compaction and recruitment of repair factors. HMGN1 may be involved in unfolding of the chromatin within the damaged area or in preventing the chromatin from re-folding. HMGN1 can affect the chromatin folding in the following ways: HMGN1 may accelerate the acetylation rate by p300. HMGN1 can prevent binding of histone H1 to the area of the lesion through competition with histone H1 for chromatin binding sites. HMGN1 can inhibit chromatin remodeling factors from re-positioning nucleosomes in the damage area. By these mechanisms HMGN1 may support chromatin de-compaction in the area of the lesion to facilitate repair of the damage. In addition p300 can acetylate HMGN1 directly to reduce the binding of HMGN1 to nucleosomes; a mode of regulation that may serve as a negative feedback loop. The dashed lines indicate hypothesized processes that have not been proven experimentally to occur following induction of DNA damage.

Fig. 2

The involvement of HMGN1 in response to DSB. A. The importance of HMGN1 to the nuclear organization of ATM under steady state conditions. Prior to any damage, the HMGN1 affects the nuclear organization of the ATM through modulation of the chromatin structure by three possible mechanisms. The first is enhancing the activity of several histone modifiers such as PCAF while inhibiting the activity of other histone modifiers such as MSK1 and RSK2. The second is direct competition with histone H1 for chromatin binding sites. The third is inhibition of chromatin remodeling factors. Through these modes of action HMGN1 may prevent incorrect retention of ATM to the chromatin fiber. Therefore, HMGN1 ensures full potential of activation for the ATM upon formation of DSB. B. The importance of HMGN1 to the cellular response to DSB. Once DSB are formed the MRN complex is recruited to the damage sites. The MRN complex activates the ATM kinase, which transduces the damage signal and activates the DDR. In addition there is a global increase in acetylation of histone H3 on Lys-14, which is dependent on HMGN1 and probably also on PCAF. Without HMGN1-dependent global chromatin re-organization, the activation of ATM is reduced by 2–3 fold. The mechanism of induction of PCAF or other HAT in response to the DSB is not known and may be dependent on the MRN complex. Histone H1 is capable of inhibiting PCAF activation as well as the global DDR. HMGN1 may prevent histone H1 interference with the DDR by direct competition for chromatin binding sites. Histone H1 binding to chromatin may be inhibited by phosphorylation by DSB-activated DNA-PK. The dashed lines indicate hypothesized processes, which have not been proven experimentally to occur following induction of DNA damage. HMT, Histone Methyl Transferase.

Fig. 3

The involvement of HMGN1 in cancer progression. HMGN1 can modulate the chromatin structure by three mechanisms. The first mechanism is enhancing the activity of several histone modifiers such as PCAF while inhibiting the activity of other histone modifiers such as MSK1 and RSK2. The second mechanism is direct competition with histone H1 for chromatin binding sites. The third mechanism is inhibition of chromatin remodeling factors. Through these modes of action HMGN1 is able to regulate the chromatin structure in promoter regions leading to activation or repression of cancer-related genes.