HMGB1: The Jack-of-All-Trades Protein Is a Master DNA Repair Mechanic

The high mobility group protein B1 (HMGB1) is a highly abundant protein with roles in several cellular processes, including chromatin structure and transcriptional regulation, as well as an extracellular role in inflammation. HMGB1's most thoroughly defined function is as a protein capable of binding specifically to distorted and damaged DNA, and its ability to induce further bending in the DNA once it is bound. This characteristic in part mediates its function in chromatin structure (binding to the linker region of nucleosomal DNA and increasing the instability of the nucleosome structure) as well as transcription (bending promoter DNA to enhance the interaction of transcription factors), but the functional consequences of HMGB1's binding to damaged DNA is still an area of active investigation. In this review we describe HMGB1's actions in the nucleotide excision repair (NER) pathway, and we discuss aspects of both the "repair shielding" and "repair enhancing" hypotheses that have been suggested. We also report information regarding HMGB1's roles in the mismatch repair (MMR), nonhomologous end-joining (NHEJ), and V(D)J recombination pathways, as well as its newly-discovered involvement in the base excision repair (BER) pathway. We further explore the potential of HMGB1 in DNA repair in the context of chromatin. The elucidation of HMGB1's role in DNA repair is critical for the complete understanding of HMGB1's intracellular functions, which is particularly relevant in the context of anti-HMGB1 therapies that are being developed to treat inflammatory diseases. (C) 2009 Wiley-Liss, Inc.