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CN-121987764-A - Application of MACIR protein in preparation of medicine for treating DNA repair and medicine thereof

CN121987764ACN 121987764 ACN121987764 ACN 121987764ACN-121987764-A

Abstract

The invention provides an application of MACIR protein in preparing a medicine for treating DNA repair and a medicine thereof, wherein the MACIR protein is taken as an adapter protein of a FIGNL-FIRRM complex, and the repair of DNA inter-strand crosslinking is promoted by enhancing the dissociation activity of the complex on RAD51 nucleoprotein filaments. In this study, in combination with proteomic analysis and genetic interaction database screening, the potential adapter protein was identified MACIR as FIGNL-FIRRM unfolding enzyme. Further studies indicate that MACIR can interact directly with FIRRM and form a ternary complex with FIGNL 1. Functionally MACIR enhances the anti-recombinant enzyme activity of FIGNL-FIRRM complex, promotes dissociation of RAD51 from DNA, thereby helping cells to cope with aldehyde-or platinum-drug-induced DNA interchain cross-linking (ICLs) damage and maintain genomic stability.

Inventors

  • CHEN YIFAN
  • GAO HUAFANG
  • WANG WEIBIN
  • ZHOU TAO

Assignees

  • 国家卫生健康委科学技术研究所

Dates

Publication Date
20260508
Application Date
20260409

Claims (8)

  1. The application of MACIR protein in preparing medicine for treating DNA repair is characterized in that MACIR protein is used as an adapter protein of FIGNL-FIRRM complex, and the repair of DNA inter-strand crosslinking is promoted by enhancing the dissociation activity of the complex on RAD51 nucleoprotein filaments.
  2. 2. The use according to claim 1, wherein the medicament is for repairing platinum-based or aldehyde-induced DNA inter-strand cross-linking (ICLs) lesions.
  3. 3. The use according to claim 1, wherein the medicament is for the treatment of diseases associated with DNA repair defects, including fanconi anemia or genomic instability induced by aldehydes.
  4. 4. A medicament for treating a disease associated with a defect in DNA repair, wherein the medicament upregulates MACIR gene expression, increases MACIR RNA expression, and/or increases MACIR protein expression.
  5. 5. The drug according to claim 4, wherein the DNA repair deficiency related diseases include Vanconi anemia or an aldehyde-induced genomic instability disease.
  6. Application of FIGNL1-FIRRM-MACIR complex in preparing medicine for treating DNA repair.
  7. 7. The use according to claim 6, wherein the medicament is for repairing platinum-based or aldehyde-induced ICL lesions.
  8. 8. The use according to claim 6, wherein the medicament is for the treatment of diseases associated with DNA repair defects, including fanconi anemia or genomic instability induced by aldehydes.

Description

Application of MACIR protein in preparation of medicine for treating DNA repair and medicine thereof Technical Field The invention relates to the technical field of biology, in particular to application of MACIR protein in preparation of a medicine for treating DNA repair and a medicine thereof. Background Inter-strand DNA cross-linking (ICLs) is a serious class of genomic DNA damage that can be induced by intracellular metabolic byproducts or exogenous deleterious chemicals, including aldehydes and platinum-based drugs. ICLs can simultaneously block DNA replication and RNA transcription, thereby resulting in DNA strand breaks and genomic instability. To cope with this injury, the cells evolved a specific repair mechanism-Vanconi anemia (FanconiAnemia, FA) pathway. This pathway coordinates the repair of ICL by a multi-step process, including activation of FA core complex, recruitment of structure-specific endonucleases to "unhook" the cross-linked structure, and repair of the consequent DNA Double Strand Breaks (DSBs) by Homologous Recombination (HR). Defects in the FA pathway can severely impair ICL repair efficiency and can lead to fanconi anemia, dysplasia, immune system disorders, or tumorigenesis. On the other hand, platinum-based chemotherapeutics treat a variety of malignancies, including ovarian cancer, by inducing accumulation of ICL lesions. In the FA pathway, the recombinase RAD51 mediates homology search, DNA pairing and strand invasion by forming nucleoprotein filaments (nucleoproteinfilaments) on single-stranded DNA (ssDNA), playing a central role in HR repair. Therefore, elucidation of molecular mechanisms that regulate RAD51 nuclear protein silk assembly and dissociation is of great importance for understanding ICL repair, maintenance of genomic stability, tumorigenesis, and chemotherapy reactions. The presently reported RAD51 regulatory mechanisms can be broadly divided into positive and negative. For example, classical cancer suppressing factors BRCA2 and BRCA1 promote assembly of RAD51 filamentous structures and enhance homologous DNA pairing. When RAD51 completes its function, helicases such as RTEL1, BLM and RECQ5 can act as anti-recombinases to dissociate the RAD51 filamentous structure in time. Notably, we and other research teams have recently discovered a novel class of anti-recombinant enzymes-FIGNL-FIRRM (also known as C1orf 112) complex, which acts by a mechanism different from all previously known RAD51 antagonists. The catalytic subunit FIGNL of the complex belongs to AAA+ATPase family, can form hexamer ring structure and combine with N end tail of RAD51, and finally realize dissociation of RAD51 filiform structure by protein unfolding mechanism through inducing conformational remodelling. Since aaa+atpase unfolding enzymes (e.g., classical p 97) typically rely on multiple adaptor proteins to recognize and remodel different substrates, exploring the presence of bridge-like adaptor proteins to specifically enhance the effect of FIGNL-FIRRM on RAD51 filaments is of great research value and helps to develop corresponding DNA drugs to treat diseases associated with DNA damage repair defects. Disclosure of Invention In order to solve the problems, the invention provides an application of MACIR protein in preparing a medicine for treating DNA repair, wherein the MACIR protein is taken as an adapter protein of a FIGNL-FIRRM complex, and the repair of DNA inter-strand crosslinking is promoted by enhancing the dissociation activity of the complex on RAD51 nucleoprotein filaments. In one embodiment, the agent is used to repair platinum-based or aldehyde-induced ICL lesions. In one embodiment, the medicament is for treating a DNA repair deficiency related disorder, including fanconi anemia or an aldehyde-induced genomic instability disorder. In one embodiment, the invention provides a medicament for treating a disease associated with a defect in DNA repair that upregulates MACIR gene expression and/or increases MACIR protein expression. In one embodiment, the invention provides the use of FIGNL-FIRRM-MACIR complex in the manufacture of a medicament for the treatment of DNA repair. Inter-strand DNA cross-linking (ICLs) is one of the most cytotoxic types of DNA damage that can block replication and transcription processes and threaten genomic stability. Its repair relies on the ordered dissociation of the RAD51 filamentous structure, a core intermediate of homologous recombination, by specialized molecular machinery. We identified MACIR/C5orf30 as a bridge-like adaptor protein for AAA+ unfolding enzymes of RAD51, revealing a novel hierarchical mechanism that regulates RAD51 dynamics and ICL repair. MACIR can bind directly to DNA and FIRRM, precisely ligating the unfolding enzyme to RAD51 filamentous structure. C5orf30, also known as macrophage immune metabolism regulatory factor (MACIR, human gene ID:285148; alias: FLJ25291, C5orf30, corresponding protein 206 amino acids), has been previous