Coming Apart at the Seams
If left uncorrected, the alkylation of DNA nucleotides can have toxic or tumorigenic effects. Fortunately, cells have a number of defense mechanisms at their disposal to address such genomic damage. For example, the human protein ALKBH2 can repair N1-methyladenine (m1A), N3-methylcytosine (m3C) and 1, N6-ethenoadenine (εA), and may potentially be a valuable safeguard against cancer.
Recent structural analyses by Yi et al. now reveal the surprisingly elegant mechanism by which this protein recognizes its target lesions. They crystallized complexes of ALKBH2 with different double-stranded DNA molecules, and observed striking differences depending on the particular base-pair situated near the protein's active site. C-G base-pairs were forced into a distorted conformation but still remained intact and fully intrahelical, whereas A-T base-pairs were actually broken, with the adenine flipped out into the active site.
The researchers suspected that this difference might arise from differences in base-pairing strength. A series of computer simulations confirmed this model, showing that the intact intrahelical arrangement was more energetically favorable for strong C-G base-pairs, while weaker base-pairings between cytosine and inosine (C-I) were energetically prone to disruption. Given that base-pairs containing alkylated bases such as m1A and m3C are generally weaker than their unmodified counterparts, this is likely to represent ALKBH2's probing mechanism.
Interestingly, this enzyme does not appear to have the capacity to check for specific types of DNA damage. Instead, it seems that the DNA rearrangements triggered during the probing process will only bring a certain subset of alkylated nucleotide types within sufficiently close proximity to the protein's catalytic repair site. This scanning and detection mechanism thus allows ALKBH2 to rapidly find and fix specific defects while causing minimal genomic disruption.— Michael Eisenstein 1
Yi, C. etal. Nat. Struct. Mol. Biol., Published online 3 June 2012, doi: 10.1038/nsmb.2320.
Trouble at the Power Plant
Parkinson's disease (PD) is associated with the ongoing loss of dopaminergic neurons within the substantia nigra pars compacta (SNc), resulting in increasingly severe motor symptoms. PD most commonly manifests in its ‘sporadic’ form, for which ageing is the greatest risk factor. However, genome-wide association studies have also revealed a number of genetic factors, which show surprising overlap with the ‘familial’ form of the disease. However, the etiology of both forms of PD appears to converge at the mitochondria, and Exner et al. have produced a review that examines the currently-available data regarding this connection.
Many of the known genetic risk factors have links to mitochondrial function. For example, parkin and PINK1—two genes associated with recessive loss-of-function parkinsonism mutations—contribute to mitochondrial biogenesis and resistance to cellular stressors, respectively. A growing body of evidence suggests that these two proteins may act within multiple common functional pathways in mitochondria. Indeed, many other genetic risk factors identified to date, such as DJ-1 and α-synuclein, may potentially affect diverse aspects of mitochondrial activity in parallel, including management of reactive oxygen species levels, mitochondrial biogenesis and mitochondrial fission and fusion, and the authors have assembled a rough map for how these various processes might interconnect. 2
In parallel, they also examine challenges associated with characterizing the role in mitochondrial dysfunction in PD. For example, it remains unclear why the dopaminergic neurons of the SNc are specifically vulnerable to these mitochondrial defects, or why some attempts to characterize risk factor gene function in fly and mammalian models have yielded seemingly contradictory results.The authors conclude that considerably more research will be required to determine the nature of the mitochondrial malfunctions that specifically contribute to the onset or progression of PD.— Michael Eisenstein
Exner, N. et al. EMBO J., Published online 26 June 2012, doi: 10.1038/emboj.2012.170.