抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The prime objective for every life form is to deliver its genetic material, intact and unchanged, to the next generation. This must be achieved despite constant assaults by endogenous and environmental agents on the DNA. To counter this threat, life has evolved several systems to detect DNA damage, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management.

/pdf/the-dna-damage-response-in-human-biology-and-disease-2gmucsko30.pdf

The DNA-damage response in human biology and disease

Double-strand DNA breaks are common events in eukaryotic cells, and there are two major pathways for repairing them: homologous recombination (HR) and nonhomologous DNA end joining (NHEJ). The various causes of double-strand breaks (DSBs) result in a diverse chemistry of DNA ends that must be repaired. Across NHEJ evolution, the enzymes of the NHEJ pathway exhibit a remarkable degree of structural tolerance in the range of DNA end substrate configurations upon which they can act. In vertebrate cells, the nuclease, DNA polymerases, and ligase of NHEJ are the most mechanistically flexible and multifunctional enzymes in each of their classes. Unlike repair pathways for more defined lesions, NHEJ repair enzymes act iteratively, act in any order, and can function independently of one another at each of the two DNA ends being joined. NHEJ is critical not only for the repair of pathologic DSBs as in chromosomal translocations, but also for the repair of physiologic DSBs created during variable (diversity) joining [V(D)J] recombination and class switch recombination (CSR). Therefore, patients lacking normal NHEJ are not only sensitive to ionizing radiation (IR), but also severely immunodeficient.

/pdf/the-mechanism-of-double-strand-dna-break-repair-by-the-2f4y3sj9kf.pdf

The Mechanism of Double-Strand DNA Break Repair by the Nonhomologous DNA End-Joining Pathway

Inflammatory conditions in selected organs increase the risk of cancer. An inflammatory component is present also in the microenvironment of tumors that are not epidemiologically related to inflammation. Recent studies have begun to unravel molecular pathways linking inflammation and cancer. In the tumor microenvironment, smoldering inflammation contributes to proliferation and survival of malignant cells, angiogenesis, metastasis, subversion of adaptive immunity, reduced response to hormones and chemotherapeutic agents. Recent data suggest that an additional mechanism involved in cancer-related inflammation (CRI) is induction of genetic instability by inflammatory mediators, leading to accumulation of random genetic alterations in cancer cells. In a seminal contribution, Hanahan and Weinberg [(2000) Cell, 100, 57-70] identified the six hallmarks of cancer. We surmise that CRI represents the seventh hallmark.

/pdf/cancer-related-inflammation-the-seventh-hallmark-of-cancer-nlqsb6p8oy.pdf

Cancer-related inflammation, the seventh hallmark of cancer: links to genetic instability.

Homologous recombination (HR) serves to eliminate deleterious lesions, such as double-stranded breaks and interstrand crosslinks, from chromosomes. HR is also critical for the preservation of repli- cation forks, for telomere maintenance, and chromosome segrega- tion in meiosis I. As such, HR is indispensable for the maintenance of genome integrity and the avoidance of cancers in humans. The HR reaction is mediated by a conserved class of enzymes termed recombinases. Two recombinases, Rad51 and Dmc1, catalyze the pairing and shuffling of homologous DNA sequences in eukaryotic cells via a filamentous intermediate on ssDNA called the presynaptic filament. The assembly of the presynaptic filament is a rate-limiting process that is enhanced by recombination mediators, such as the breast tumor suppressor BRCA2. HR accessory factors that facil- itate other stages of the Rad51- and Dmc1-catalyzed homologous DNA pairing and strand exchange reaction have also been identified. Recent progress on elucidating the mechanisms of action of Rad51 and Dmc1 and their cohorts of ancillary factors is reviewed here.

https://www.med.nyu.edu/klein/PDFs/annurev.biochem.77.061306.125255.pdf

Mechanism of eukaryotic homologous recombination.

Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide.

The HOP2 and MND1 genes are indispensable for meiotic recombination. The products of these genes associate to form a stable heterodimeric complex that binds DNA and stimulates the recombinase activity of Rad51 and Dmc1. Here we conduct molecular studies to delineate the action mechanism of the Hop2–Mnd1 complex. We present evidence to implicate Hop2 as the major DNA-binding subunit and Mnd1 as the prominent Rad51 interaction entity. Hop2–Mnd1 stabilizes the Rad51–single-stranded DNA (ssDNA) nucleoprotein filament, the catalytic intermediate in recombination reactions. We also show that Hop2–Mnd1 enhances the ability of the Rad51–ssDNA nucleoprotein filament to capture duplex DNA, an obligatory step in the formation of the synaptic complex critical for DNA joint formation. Thus, our results unveil a bipartite mechanism of Hop2–Mnd1 in homologous DNA pairing: stabilization of the Rad51 presynaptic filament and duplex DNA capture to enhance synaptic complex formation.

/pdf/bipartite-stimulatory-action-of-the-hop2-mnd1-complex-on-the-5g1peztk16.pdf

Bipartite stimulatory action of the Hop2–Mnd1 complex on the Rad51 recombinase

https://digital.library.unt.edu/ark:/67531/metadc896466/m2/1/high_res_d/932500.pdf

Joseph San Filippo

Papers

Mechanism of eukaryotic homologous recombination.

Promotion of BRCA2-Dependent Homologous Recombination by DSS1 via RPA Targeting and DNA Mimicry

Recombination mediator and Rad51 targeting activities of a human BRCA2 polypeptide.

Bipartite stimulatory action of the Hop2–Mnd1 complex on the Rad51 recombinase

Promotion of Homologous Recombination and Genomic Stability by RAD51AP1 via RAD51 Recombinase Enhancement