HMGN (High-Mobility Group Nucleosome-binding) proteins are members of the broader class of high-mobility group (HMG) chromosomal proteins that are involved in regulation of transcription, replication, recombination, and DNA repair. HMGN1 and HMGN2 (initially designated HMG-14 and HMG-17 respectively) were discovered by E.W. Johns research group in the early 1970s. HMGN3, HMGN4, and HMGN5 were discovered later and are less abundant. HMGNs are nucleosome binding proteins that help in transcription, replication, recombination, and DNA repair. They can also alter the chromatin epigenetic landscape, helping to stabilize cell identity. There is still relatively little known about their structure and function. HMGN proteins are found in all vertebrates, and play a role in chromatin structure and histone modification. HMGNs come in long chains of amino acids, containing around 100 for HMGN1-4, and roughly 200 in HMGN5. Recent research on the HMGN family is focused on their effect on cell identity, and how reduction of HMGNs relates to induced reprogramming of mouse embryonic fibroblasts (MEFs).
Function Much of the research that has been done HMGN proteins have been done in vitro, while there is relatively little on the in vivo function and roles of HMGN proteins. Due to these proteins being predominantly found in higher eukaryotes, the use of microorganisms and other lower eukaryotes has deemed insufficient to determine the in vivo roles of HMGN proteins. A study was done with knockout mice to see the effect if any that HMGN proteins play on a full organism level. This resulted in the mice showing increasing sensitivity to UV radiation when having less than normal levels of HMGN(2). This would indicate that HMGN might facilitate repair of UV damage. The same increase in sensitivity was observed in mice when exposed to gamma radiation, however the cellular processes that repair DNA in either case are drastically different, leading to an inconclusive state whether HMGN proteins facilitate DNA repair in vivo. HMGN1 and HMGN2 do not co-localize within living cells. This is indication of possible different roles of each HMGN.
Family
HMGN proteins are part of broader group of proteins referred to as High Mobility group chromosomal (HMG) proteins. This larger group was named this for their high electrophoretic mobility in polyacrylamide gels and is differentiated into 3 distinct but related groups, one of them being HMGN proteins. HMGN family can be further divided into specific proteins, these being HMGN1, HMGN2, HMGN3, HMGN4, and HMGN5. The overall sizes of the proteins vary to each specific one, but HMGN1-4 average 100 amino acids. Whereas the larger HMGN5 proteins are 300+ amino acids long in mice and roughly 200 in length for humans.
HMGN 1 and HMGN 2 HMGN1 and HMGN2 are among the most common of the HMGN proteins. The main purpose and function are reducing the compaction of the cellular chromatin by nucleosome binding. NMR evidence shows that reducing compaction occurs when the proteins targets the main elements that are responsible for the compactions of the chromatin. These have an expression rates that correlate to the differentiation of the cells it is present in. Areas that have experienced differentiation have reduced expression levels in comparison to undifferentiated areas, where HMGN1 and HMGN2 are highly expressed.
HMGN 3 HMGN3 has two variants, HMGN3a and HMGN3b. Unlike the HMGN1 and HMGN2 proteins, both forms of HMGN3 tend to be tissue and development specific. They are only expressed in certain tissues at specific developmental stages. There is no preference to a certain tissue given by the two variants of the HMGN3 proteins. There is equal likelihood that either be present in a certain highly expressed HMGN3 tissue. The brain and the eyes in particular are areas that HMGN3 is heavily expressed as well as in adult pancreatic islet cells. It has been shown that the loss of HMGN3 in mice has led to a mild onset of diabetes due to ineffective insulin secretion.
HMGN 4 The discovery of HMGN4 was done by GenBank during a database search and identified it as a "new HMGN2 like transcript", indicating that HMGN4 is closely related to HMGN2. There has been very little research done on HMGN4 proteins. The gene associated with the production of the HMGN4 is located in a region associated with schizophrenia on chromosome 6. Until this point every kind of HMGN has been identified in the vertebrates, but HMGN4 has only been seen and identified in primates. Within humans, HMGN4 has shown high levels of expression in the thyroid, thymus and the lymph nodes.
HMGN 5 The most recent addition to the HMGN protein family is of HMGN5. It is larger than the previous HMGNs, containing 300+ amino acids, due to a long C-terminal domain that varies with species, explaining why mice and humans have a different size of HMGN5. Its biological function is unknown but has shown expression in placental development. There have also been cases where HMGN5 was present in human tumors including, prostate cancer, breast cancer, lung cancer, etc. For this reason, it is thought that HMGN5 might have some link to cancer and might be a potential target for cancer therapy in the future.
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