Somatic Hypermutation - an overview

Authored by sciencedirect.com and submitted by wattnurt

CSR and SHM were previously thought to be mediated by different mechanisms, and the requirement of AID for both events surprised many scientists in the field. However, when we carefully compare the two events, they share several features that are critical to the molecular mechanisms of SHM and CSR. The targets of CSR and SHM must be transcribed before the reaction takes place. The efficiency of these genetic alterations is correlated with the level of transcription. The targets of both events do not have specific primary sequences, yet defined DNA regions are altered. Not only SHM but also CSR is associated with mutations. Most important, they both require AID activity.

CSR has important features mechanistically distinct from SHM. Not only do the products of CSR and SHM differ but also the initiation of the two events is dissimilar. CSR requires two DSBs, one each in two different S regions. By contrast, SHM is more likely to be initiated by a single nick on one strand of the target DNA (Faili et al., 2002b). During CSR, two separate DNA ends, which originally can be located 100 kb apart, have to be held in a close proximity. Without proteins that can hold the two recombining ends close together, it is probably impossible to join the DNA ends. It is therefore reasonable to assume that CSR depends on a protein complex that differs from a SHM complex. The CSR complex, which we refer to as “recombinasome,” may contain AID or the putative protein encoded by the mRNA it edits, MMR proteins, base excision repair enzymes, error-prone DNA polymerases, and NHEJ proteins. Although SHM may not require a complex of proteins involved in DNA synapsis, the “mutasome” may contain the DNA nicking enzyme, MMR, base excision repair enzymes, and error-prone DNA polymerases. Additional components in these complexes may be required to target them to the correct DNA segments.

During evolution, SHM appeared first in cartilaginous and bony fish, whereas these fish do not appear to have CSR (Litman et al., 1999; Flajnik, 2002). Amphibians, which evolved later, were the first to carry out both CSR and SHM. Another indication of the distinct functions of AID for CSR and SHM is found in hyper-IgM type II patients with mutations in AID who have significant levels of SHM, but almost no CSR (Revy et al., 2000). The results can be explained most easily by the possibility that AID interacts with different protein molecules when inducing SHM and CSR. Perhaps, in these patients, proteins required for CSR are unable to associate with the mutated AID, whereas proteins required for SHM interact normally. In addition, CSR and SHM are independently regulated. For example, LPS stimulation of splenic B cells efficiently induces CSR but very rarely SHM. Thus, although a single protein, AID, mediates both CSR and SHM, the two processes evolved stepwise and are regulated differently, although it is possible that in germinal center cells they occur concurrently. Altogether, the data suggest that CSR and SHM are likely to have different molecular mechanisms downstream of AID.

HedonicSatori on April 15th, 2021 at 04:31 UTC »

Immunologist here.

This is one of the things that made me fall in love with immunology when it was first explained to me. The immune system is fucking insane. It's as complex as your brain and it also moves around. It adapts itself to whatever your body needs. It acts like an alien colonizer tending us like we're a complex bonsai: in every disease and normal function we look at, the immune system is up to something. Healing your wounds? Of course, no problem, gonna have a bunch of tissue resident immune sentinels scream until other specialized tanks show up and sterilize the wound, triage the wound site, and then lay down the healing architecture (which they then guide). Trying to get yolked? Immune system is right there with muscle stem cell regulation and myofibril recovery (not to mention metabolism). Trying to lose weight? Gonna have to ask your adipocyte-associated macrophages for permission first, get them to poke the fat cells into action and stop being hoarders. Getting pregnant? Yup, you guessed it, there's the immune system literally remodeling your uterus to prepare it for Das Fetus. It's everywhere, in everything, and it is gloriously weird and fascinating and I am loving banging my head against it trying to imagine what kinds of "thoughts" the immune system is thinking (there is significant evidence of several forms of biological computation taking place in the immune system).

JamesIgnatius27 on April 14th, 2021 at 23:29 UTC »

https://en.wikipedia.org/wiki/Somatic_hypermutation

In case anybody wants the wikipedia on the process. It's called somatic hypermutation.

cagranconniferim on April 14th, 2021 at 22:55 UTC »

That sounds like the biological equivalent of button-mashing