RGD Reference Report - Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia. - Rat Genome Database

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Increased intranuclear matrix metalloproteinase activity in neurons interferes with oxidative DNA repair in focal cerebral ischemia.

Authors: Yang, Y  Candelario-Jalil, E  Thompson, JF  Cuadrado, E  Estrada, EY  Rosell, A  Montaner, J  Rosenberg, GA 
Citation: Yang Y, etal., J Neurochem. 2010 Jan;112(1):134-49. Epub 2009 Oct 15.
RGD ID: 2325713
Pubmed: PMID:19840223   (View Abstract at PubMed)
PMCID: PMC4950937   (View Article at PubMed Central)
DOI: DOI:10.1111/j.1471-4159.2009.06433.x   (Journal Full-text)

Increased matrix metalloproteinase (MMP) activity is implicated in proteolysis of extracellular matrix in ischemic stroke. We recently observed intranuclear MMP activity in ischemic brain neurons at early reperfusion, suggesting a possible role in nuclear matrix proteolysis. Nuclear proteins, poly-ADP-ribose polymerase-1 (PARP-1) and X-ray cross-complementary factor 1 (XRCC1), as well as DNA repair enzymes, are important in DNA fragmentation and cell apoptosis. We hypothesized that intranuclear MMP activity facilitates oxidative injury in neurons during early ischemic insult by cleaving PARP-1 and XRCC1, interfering with DNA repair. We induced a 90-min middle cerebral artery occlusion in rats. Increase activity of MMP-2 and -9, detected in the ischemic neuronal nuclei at 3 h, was associated with DNA fragmentation at 24 and 48 h reperfusion. The intranuclear MMPs cleaved PARP-1. Treatment of the rats with a broad-spectrum MMP inhibitor, BB1101, significantly attenuated ischemia-induced PARP-1 cleavage, increasing its activity. Degradation of XRCC1 caused by ischemic insult in rat brain was also significantly attenuated by BB1101. We found elevation of oxidized DNA, apurinic/apyrimidinic sites, and 8-hydroxy-2'-deoxyguanosine, in ischemic brain cells at 3 h reperfusion. BB1101 markedly attenuated the early increase of oxidized DNA. Using tissue from stroke patients, we found increased intranuclear MMP expression. Our data suggest that intranuclear MMP activity cleaves PARP-1 and XRCC1, interfering with oxidative DNA repair. This novel role for MMPs could contribute to neuronal apoptosis in ischemic injuries.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Objects Annotated

Genes (Rattus norvegicus)
Mmp2  (matrix metallopeptidase 2)
Parp1  (poly (ADP-ribose) polymerase 1)
Xrcc1  (X-ray repair cross complementing 1)

Genes (Mus musculus)
Mmp2  (matrix metallopeptidase 2)
Parp1  (poly (ADP-ribose) polymerase family, member 1)
Xrcc1  (X-ray repair complementing defective repair in Chinese hamster cells 1)

Genes (Homo sapiens)
MMP2  (matrix metallopeptidase 2)
PARP1  (poly(ADP-ribose) polymerase 1)
XRCC1  (X-ray repair cross complementing 1)


Additional Information