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

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.

https://www.cell.com/trends/cell-biology/pdf/S0962-8924(15)00142-7.pdf

Repair Pathway Choices and Consequences at the Double-Strand Break

Homologous recombination (HR) is required for accurate chromosome segregation during the first meiotic division and constitutes a key repair and tolerance pathway for complex DNA damage, including DNA double-strand breaks, interstrand crosslinks, and DNA gaps. In addition, recombination and replication are inextricably linked, as recombination recovers stalled and broken replication forks, enabling the evolution of larger genomes/replicons. Defects in recombination lead to genomic instability and elevated cancer predisposition, demonstrating a clear cellular need for recombination. However, recombination can also lead to genome rearrangements. Unrestrained recombination causes undesired endpoints (translocation, deletion, inversion) and the accumulation of toxic recombination intermediates. Evidently, HR must be carefully regulated to match specific cellular needs. Here, we review the factors and mechanistic stages of recombination that are subject to regulation and suggest that recombination achieves fle...

/pdf/regulation-of-homologous-recombination-in-eukaryotes-1gspqbb11k.pdf

Regulation of homologous recombination in eukaryotes

Homologous recombination (HR) comprises a series of interrelated pathways that function in the repair of DNA double-stranded breaks (DSBs) and interstrand crosslinks (ICLs). In addition, recombination provides critical support for DNA replication in the recovery of stalled or broken replication forks, contributing to tolerance of DNA damage. A central core of proteins, most critically the RecA homolog Rad51, catalyzes the key reactions that typify HR: homology search and DNA strand invasion. The diverse functions of recombination are reflected in the need for context-specific factors that perform supplemental functions in conjunction with the core proteins. The inability to properly repair complex DNA damage and resolve DNA replication stress leads to genomic instability and contributes to cancer etiology. Mutations in the BRCA2 recombination gene cause predisposition to breast and ovarian cancer as well as Fanconi anemia, a cancer predisposition syndrome characterized by a defect in the repair of DNA interstrand crosslinks. The cellular functions of recombination are also germane to DNA-based treatment modalities of cancer, which target replicating cells by the direct or indirect induction of DNA lesions that are substrates for recombination pathways. This review focuses on mechanistic aspects of HR relating to DSB and ICL repair as well as replication fork support.

/pdf/homologous-recombination-in-dna-repair-and-dna-damage-2ba9enej2s.pdf

Homologous recombination in DNA repair and DNA damage tolerance

Rad51, Rad52, and RPA play central roles in homologous DNA recombination. Rad51 mediates DNA strand exchange, a key reaction in DNA recombination. Rad52 has two distinct activities: to recruit Rad51 onto single-strand (ss)DNA that is complexed with the ssDNA-binding protein, RPA, and to anneal complementary ssDNA complexed with RPA. Here, we report that Rad52 promotes annealing of the ssDNA strand that is displaced by DNA strand exchange by Rad51 and RPA, to a second ssDNA strand. An RPA that is recombination-deficient (RPA(rfa1-t11)) failed to support annealing, explaining its in vivo phenotype. Escherichia coli RecO and SSB proteins, which are functional homologues of Rad52 and RPA, also facilitated the same reaction, demonstrating its conserved nature. We also demonstrate that the two activities of Rad52, recruiting Rad51 and annealing DNA, are coordinated in DNA strand exchange and second ssDNA capture.

/pdf/rad52-mediated-dna-annealing-after-rad51-mediated-dna-strand-1ga5brzzj2.pdf

Rad52-mediated DNA annealing after Rad51-mediated DNA strand exchange promotes second ssDNA capture

http://microbiology.ucdavis.edu/kowalczykowski/PDF_files/M801097200v1.pdf

Rad51 Protein Controls Rad52-mediated DNA Annealing

In Saccharomyces cerevisiae, a Cdc13–Est1 interaction is proposed to mediate recruitment of telomerase to DNA ends. Here we provide unique in vitro evidence for this model by demonstrating a direct interaction between purified Cdc13 and Est1. The Cdc13–Est1 interaction is specific and requires the in vivo defined Cdc13 recruitment domain. Moreover, in the absence of this interaction, Est1 is excluded from telomeric single-stranded (ss)DNA. The apparent association constand (Kd) between Est1 and a Cdc13-telomeric ssDNA complex was ∼250 nM. In G2 phase cells, where telomerase is active, Cdc13 and Est1 were sufficiently abundant (∼420 and ∼110 copies per cell, respectively) to support complex formation. Interaction between Cdc13 and Est1 was unchanged by three telomerase-deficient mutations, Cdc13E252K (cdc13-2), Est1K444E (est1-60), and Cdc13S249,255D, indicating that their telomerase null phenotypes are not due to loss of the Cdc13–Est1 interaction. These data recapitulate in vitro the first step in telomerase recruitment to telomeric ssDNA and suggest that this step is necessary to recruit telomerase to DNA ends.

https://www.pnas.org/content/pnas/108/51/20362.full.pdf

The telomeric Cdc13 protein interacts directly with the telomerase subunit Est1 to bring it to telomeric DNA ends in vitro

http://microbiology.ucdavis.edu/kowalczykowski/PDF_files/Wu%20et%20al.%20(2006)%20M601827200v1.pdf

Yun Wu

Papers

Rad52-mediated DNA annealing after Rad51-mediated DNA strand exchange promotes second ssDNA capture

Rad51 Protein Controls Rad52-mediated DNA Annealing

The telomeric Cdc13 protein interacts directly with the telomerase subunit Est1 to bring it to telomeric DNA ends in vitro

DNA Annealing Mediated by Rad52 and Rad59 Proteins

RecFOR Proteins Target RecA Protein to a DNA Gap with Either DNA or RNA at the 5′ Terminus IMPLICATION FOR REPAIR OF STALLED REPLICATION FORKS