Interactions of high mobility group box protein 1 (HMGB1) with nucleic acids: Implications in DNA repair and immune responses

Abstract

High mobility group box protein 1 (HMGB1) is a highly versatile, abundant, and ubiquitously expressed, non-histone chromosomal protein, which belongs to the HMGB family of proteins. These proteins form an integral part of the architectural protein repertoire to support chromatin structure in the nucleus. In the nucleus, the role of HMGB1 is attributed to its ability to bind to undamaged DNA, damaged DNA, and alternative (i.e. non-B) DNA structures with high affinity and subsequently induce bending of the DNA substrates. Due to its binding to DNA, HMGB1 has been implicated in critical biological processes, such as DNA transcription, replication, repair, and recombination. In addition to its intracellular functions, HMGB1 can also be released in the extracellular space where it elicits immunological responses. HMGB1 associates with many different molecules, including DNA, RNA, proteins, and lipopolysaccharides to modulate a variety of processes in both DNA metabolism and in innate immunity. In this review, we will focus on the implications of the interactions of HMGB1 with nucleic acids in DNA repair and immune responses. We report on the roles of HMGB1 in nucleotide excision repair (NER), base excision repair (BER), mismatch repair (MMR) and DNA double-strand break repair (DSBR). We also report on its roles in immune responses via its potential effects on antigen receptor diversity generation [V(D)J recombination] and interactions with foreign and self-nucleic acids. HMGB1 expression is altered in a variety of cancers and immunological disorders. However, due to the diversity and complexity of the biological processes influenced by HMGB1 (and its family members), a detailed understanding of the intracellular and extracellular roles of HMGB1 in DNA damage repair and immune responses is warranted to ensure the development of effective HMGB1-related therapies.

Keywords: Autoimmunity; DNA damage; DNA repair; High mobility group box 1 protein (HMGB1); V(D)J recombination.

Figure 1:

Schematic of HMGB1 protein. The HMGB1 protein has two positively charged domains; BOX A and BOX B, and a negatively charged acidic C-terminal tail. The two domains along with the C-terminal tail play a role in the binding and bending of DNA.

Figure 2:. HMGB1 modified forms.

A) HMGB1 oxidized: HMGB1 has three cysteine residues, two C23 and C45 in the Box A domain and one C106 in the Box B domain. B) HMGB1 disulfide modified: an intermolecular disulfide bond can be formed between C23 and C45 of HMGB1, while C106 is in the reduced form.

Figure 3:. HMGB1-mediated modulation of DNA repair and chromatin remodeling.

Upon DNA damage, distortions are caused due to formation of DNA lesions. Further DNA distortions are introduced upon binding of HMGB1 to these lesions. HMGB1 can then interact with different DNA repair proteins and chromatin remodeling factors, which favors the repair of damaged DNA. Figure reused from ref 25. S.S. Lange, D.L. Mitchell, K.M. Vasquez, High mobility group protein B1 enhances DNA repair and chromatin modification after DNA damage, Proc Natl Acad Sci U S A, 105 (2008) 10320–10325. (Copyright (2008) National Academy of Sciences, U.S.A.).

Figure 4:. Dynamics of interactions of the acidic C-terminal tail of HMGB1 with Box A and Box B, and linker histone H1.

The C-terminal tail of HMGB1 binds to the DNA-binding domains of HMGB1, restricting their interaction with DNA. However, the acidic tail of HMGB1 can interact with the basic tail of histone H1, thereby disrupting its interaction with the DNA-binding domains of HMGB1. This interaction can therefore lower the affinity of H1 for DNA and it can be displaced from the DNA by HMGB1, thereby facilitating binding of HMGB1 to DNA.

Figure 5:. Overview of cellular responses resulting from interactions of HMGB1 with nucleic acids.

Interactions of HMGB1 with nucleic acids/nucleosomes can affect a variety of cellular processes. In the nucleus, the interactions of HMGB1 with DNA can impact architecture and consequently affect transcription, chromatin remodeling, DNA repair pathways (NER, BER, MMR, DSBR), and V(D)J recombination. In the extracellular space, CpG DNA released, for example by bacteria, can bind HMGB1 and subsequently engage the RAGE receptors located on the cell surface. This complex is internalized into the endosomes where it can bind the TLR9 receptor and activate a cascade of reactions resulting in activation of IFNα and functions as a driver of innate immunity. HMGB1 can interact with nucleosomes to form immune complexes released from apoptotic cells in autoimmune diseases (e.g. SLE). In this case as well, the immune complexes can engage RAGE and subsequently bind TLR9 to activate production of IFNα and thereby function in the pathogenesis of autoimmune disorders. HMGB1 can also function as a sensor of cytosolic DNA in conjunction with cGAS and TFAM.