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Foreign Office minister Mark Simmonds quits the government and is standing down as an MP at the next general election.
The Africa minister’s departure is a fresh blow to David Cameron following the resignation of Baroness Warsi in protest at the government’s policy on Gaza.
Downing Street said Mr Simmonds’ departure had been agreed “some weeks ago” but the announcement had been delayed to allow him to chair a United Nations session on the situation in the Democratic Republic of Congo.
Read more: 'Why I quit over Gaza' - Baroness Warsi
In his resignation letter, Boston and Skegness MP Mr Simmonds told David Cameron he would “remain supportive of you, your government and the Conservative Party”.
The prime minister said Mr Simmonds still had “much more to give” and had been an “incredibly loyal colleague, but also a good friend”.
Mr Simmonds will be replaced at the Foreign Office by Tory MP James Duddridge.
Mr Simmonds came under-fire during the 2014 European elections, when Ukip won 52 per cent of the vote in the Borough of Boston. This was the highest share of the vote achieved by the party in the country.
Following the result, Peter Bedford, the Leader of Boston Borough Council, criticised Mr Simmonds saying that he “should be worried” about the threat of Ukip at the next general election.