Understanding Rad51 function is a prerequisite for progress in cancer research.

Bengt Nordén,Masayuki Takahashi

doi:10.1017/qrd.2020.13

Bengt Nordén, Masayuki Takahashi

Open Access

https://doi.org/10.1017/qrd.2020.13

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Abstract

The human protein Rad51 is double-edged in cancer contexts: on one hand, preventing tumourigenesis by eliminating potentially carcinogenic DNA damage and, on the other, promoting tumours by introducing new mutations. Understanding mechanistic details of Rad51 in homologous recombination (HR) and repair could facilitate design of novel methods, including CRISPR, for Rad51-targeted cancer treatment. Despite extensive research, however, we do not yet understand the mechanism of HR in sufficient detail, partly due to complexity, a large number of Rad51 protein units being involved in the exchange of long DNA segments. Another reason for lack of understanding could be that current recognition models of DNA interactions focus only on hydrogen bond-directed base pair formation. A more complete model may need to include, for example, the kinetic effects of DNA base stacking and unstacking ('longitudinal breathing'). These might explain how Rad51 can recognize sequence identity of DNA over several bases long stretches with high accuracy, despite the fact that a single base mismatch could be tolerated if we consider only the hydrogen bond energy. We here propose that certain specific hydrophobic effects, recently discovered destabilizing stacking of nucleobases, may play a central role in this context for the function of Rad51.

Highlights

Cancer is a genetic disease in the sense that it is induced by modification of genetic information in genes involved in regulating cell proliferation resulting in uncontrolled cell proliferation, a landmark of tumour
Modification could be caused by replication errors; this is, very rare because the high fidelity of DNA replication is maintained by DNA polymerase itself, its proofreading functions and other surveillance systems such as mismatch-repair systems (Kunkel, 2004; Bębenek and Graczyk, 2018)
Double-strand breaks cannot be fixed in this manner and are instead repaired by non-homologous end-joining (NHEJ), Bengt Nordén and Masayuki Takahashi microhomology-mediated end-joining or homologous recombination (HR) (Jasin and Rothstein, 2013; Wright et al, 2018)

Summary

Replication errors

Cancer is a genetic disease in the sense that it is induced by modification of genetic information (the nucleotide sequence) in genes involved in regulating cell proliferation resulting in uncontrolled cell proliferation, a landmark of tumour. Individuals with inherited mutations in mismatch repair enzymes seem prone to developing colorectal cancer Another cause that increases replication errors is DNA damage as we will touch upon below. By exchanging a broken strand for an undamaged homologous strand, HR can repair double-strand breaks usually without causing any genetic modification and, in this way, prevent mutation. Mutations are rare and usually affect only one copy of a gene, and it is likely that any given mutation will be masked by the presence of the ‘healthy’ gene, with the exception of dominant phenotypes such as predisposition to breast cancer caused by Schematic presentation of Rad51-promoted DNA strand exchange reaction ssDNA presynaptic complex binding of Rad.

Cancer formation

Findings

Reaction mechanism